subject:(Amyloid precursor protein)

University of Adelaide

1. Corrigan, Frances. The role of the amyloid precursor protein following traumatic brain injury.

Degree: 2011, University of Adelaide

► The amyloid precursor protein (APP) is known to increase following traumatic brain injury (TBI). It has been hypothesised that this increase in APP may be… (more)

▼ The amyloid precursor protein (APP) is known to increase following traumatic brain injury (TBI). It has been hypothesised that this increase in APP may be deleterious to outcome due to the production of neurotoxic Aβ. Conversely, this upregulation may be beneficial as cleavage of APP via the alternative non-amyloidogenic pathway produces the soluble alpha form of APP (sAPPα), which is known to have many neuroprotective and neurotrophic functions. Indeed a previous study showed that treatment with sAPPα following a diffuse injury in rats reduced apoptotic cell death and axonal injury which corresponded with an improvement in motor outcome. However, it is not yet known whether endogenous APP plays a similar beneficial role following TBI, or which specific region within sAPPα conferred this protective activity. In order to investigate this the effect of post-traumatic administration of various regions within sAPPα was examined following severe-impact acceleration TBI in Sprague Dawley rats. Furthermore the outcome of male C57BL6j x 129sv APP-/- mice was compared to that of APP+/+ mice following two types of traumatic brain injury; a diffuse lesion caused by a weight drop model and a focal lesion induced by a controlled cortical impact (CCI) injury. Knockout of APP was found to worsen outcome following both a mild diffuse and moderate focal injury, with an exacerbation of motor and cognitive deficits associated with an increase in neuronal injury and an impaired reparative response. These deficits could be rescued with treatment with sAPPα, suggesting that it was lack of this APP metabolite which caused the increase in vulnerability of APP-/- mice. Furthermore initial investigations in Sprague Dawley rats found that only the domains of sAPPα that contained heparin binding sites were able to improve functional outcome and decrease axonal injury following diffuse TBI. This suggested that the neuroprotective activity of sAPPα related to its ability to bind to heparin sulphate proteoglycans. Indeed a preliminary investigation found that the peptide APP96-110, which encompassess one of the heparin binding sites within sAPPα, was sufficient to reduce functional deficits and neuronal injury in APP-/- mice. These results demonstrate that the upregulation of APP seen following TBI is a protective response, with the benefits of sAPPα outweighing any negative effects of other APP metabolites like Aβ. The neuroprotective properties of sAPPα, may relate to its heparin binding sites, with one of these regions, APP96-110, warranting further investigation as a putative neuroprotective agent following TBI. Advisors/Committee Members: Van Den Heuvel, Corinna (advisor), Vink, Robert (advisor), School of Medical Sciences (school).

Subjects/Keywords: amyloid precursor protein; traumatic brain injury; sAPPα

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Corrigan, F. (2011). The role of the amyloid precursor protein following traumatic brain injury. (Thesis). University of Adelaide. Retrieved from http://hdl.handle.net/2440/80625

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Corrigan, Frances. “The role of the amyloid precursor protein following traumatic brain injury.” 2011. Thesis, University of Adelaide. Accessed April 10, 2021. http://hdl.handle.net/2440/80625.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Corrigan, Frances. “The role of the amyloid precursor protein following traumatic brain injury.” 2011. Web. 10 Apr 2021.

Vancouver:

Corrigan F. The role of the amyloid precursor protein following traumatic brain injury. [Internet] [Thesis]. University of Adelaide; 2011. [cited 2021 Apr 10]. Available from: http://hdl.handle.net/2440/80625.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Corrigan F. The role of the amyloid precursor protein following traumatic brain injury. [Thesis]. University of Adelaide; 2011. Available from: http://hdl.handle.net/2440/80625

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

2. Puig, Kendra L. Role Of The Alzheimer's Amyloid Precursor Protein In High Fat Diet Induced Obesity And Regulating Macrophage Phenotype.

Degree: PhD, Biomedical Sciences, 2013, University of North Dakota

URL: https://commons.und.edu/theses/1469

► Amyloid precursor protein (APP) derived amyloid beta peptides have been extensively investigated in Alzheimer's disease pathology of the brain. However, the function of full… (more)

▼ Amyloid precursor protein (APP) derived amyloid beta peptides have been extensively investigated in Alzheimer's disease pathology of the brain. However, the function of full length APP in the central nervous system remains unclear. Even less is known about the behavior of this ubiquitously expressed protein and it metabolites outside of the central nervous system. Therefore, we sought to broaden our understanding of the expression and function of APP and its proteolytic fragments in specific non-neuronal tissues. Although the majority of research effort is currently focused on neuronal amyloid beta production and its effects on cells, prior work in our lab demonstrated a novel role for APP in regulating the phenotype of monocytic lineage cells. Therefore, we hypothesized that APP can behave as a proinflammatory receptor on these cells involved in modulating their tissue infiltration and differentiation. Based upon the fact that midlife obesity is a risk factor for Alzheimer's disease and both obese adipose tissue and Alzheimer's disease brains share a common presence of increased, reactive macrophage and microglia, respectively, we hypothesized that APP may have a common role in both diseases regulating the infiltration or proinflammatory activation of microglia and macrophage characterizing both diseases. Indeed, recent data has demonstrated that APP levels are increased in adipose tissue from obese versus control individuals. To test this idea we utilized a high fat diet feeding paradigm on both C57BL6 wild type and APP-/- mice to examine any role for APP and high fat diet dependent changes in adipose tissue, brain, and intestine. In vivo changes were compared to those obtained using primary cells isolated from the murine models. Collectively, these data suggest that APP does regulate microglia and macrophage phenotype in a manner responsible for altering their behavior in tissue specific fashion. This suggests that immune-related functions of APP may be a common type of pathophysiology linking the complex diseases of obesity and Alzheimer's disease. Advisors/Committee Members: Colin K. Combs.

Subjects/Keywords: amyloid precursor protein; inflammation; intestine; macrophage; obesity

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Puig, K. L. (2013). Role Of The Alzheimer's Amyloid Precursor Protein In High Fat Diet Induced Obesity And Regulating Macrophage Phenotype. (Doctoral Dissertation). University of North Dakota. Retrieved from https://commons.und.edu/theses/1469

Chicago Manual of Style (16^th Edition):

Puig, Kendra L. “Role Of The Alzheimer's Amyloid Precursor Protein In High Fat Diet Induced Obesity And Regulating Macrophage Phenotype.” 2013. Doctoral Dissertation, University of North Dakota. Accessed April 10, 2021. https://commons.und.edu/theses/1469.

MLA Handbook (7^th Edition):

Puig, Kendra L. “Role Of The Alzheimer's Amyloid Precursor Protein In High Fat Diet Induced Obesity And Regulating Macrophage Phenotype.” 2013. Web. 10 Apr 2021.

Vancouver:

Puig KL. Role Of The Alzheimer's Amyloid Precursor Protein In High Fat Diet Induced Obesity And Regulating Macrophage Phenotype. [Internet] [Doctoral dissertation]. University of North Dakota; 2013. [cited 2021 Apr 10]. Available from: https://commons.und.edu/theses/1469.

Council of Science Editors:

Puig KL. Role Of The Alzheimer's Amyloid Precursor Protein In High Fat Diet Induced Obesity And Regulating Macrophage Phenotype. [Doctoral Dissertation]. University of North Dakota; 2013. Available from: https://commons.und.edu/theses/1469

University of Melbourne

3. SPOERRI, LOREDANA. Investigating the functional role of the amyloid precursor protein’s copper binding domain.

Degree: 2011, University of Melbourne

URL: http://hdl.handle.net/11343/36752

► Alzheimer’s disease is a progressive and eventually fatal neurodegenerative disorder characterized by specific proteins deposition in the brain: amyloid plaques and tau tangles. While age… (more)

Subjects/Keywords: amyloid precursor protein; copper binding domain

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

SPOERRI, L. (2011). Investigating the functional role of the amyloid precursor protein’s copper binding domain. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/36752

Chicago Manual of Style (16^th Edition):

SPOERRI, LOREDANA. “Investigating the functional role of the amyloid precursor protein’s copper binding domain.” 2011. Doctoral Dissertation, University of Melbourne. Accessed April 10, 2021. http://hdl.handle.net/11343/36752.

MLA Handbook (7^th Edition):

SPOERRI, LOREDANA. “Investigating the functional role of the amyloid precursor protein’s copper binding domain.” 2011. Web. 10 Apr 2021.

Vancouver:

SPOERRI L. Investigating the functional role of the amyloid precursor protein’s copper binding domain. [Internet] [Doctoral dissertation]. University of Melbourne; 2011. [cited 2021 Apr 10]. Available from: http://hdl.handle.net/11343/36752.

Council of Science Editors:

SPOERRI L. Investigating the functional role of the amyloid precursor protein’s copper binding domain. [Doctoral Dissertation]. University of Melbourne; 2011. Available from: http://hdl.handle.net/11343/36752

4. Luu, Luan. Defining the function of Amyloid Precursor Protein dimerisation in neuritogenesis.

Degree: 2017, University of Melbourne

URL: http://hdl.handle.net/11343/194187

► Amyloid Precursor Protein (APP) is known to be primarily involved with Alzheimer’s disease; however APP is also involved with neurogenesis, synaptic plasticity and neuroprotection. Many… (more)

▼ Amyloid Precursor Protein (APP) is known to be primarily involved with Alzheimer’s disease; however APP is also involved with neurogenesis, synaptic plasticity and neuroprotection. Many factors can bind to APP to affect its function and processing. APP can also bind to other membrane bound APP, known as APP dimerisation. We hypothesise that dimerisation of APP can affect the biological actions of APP. This study aims to determine the effect APP dimerisation has on neurite outgrowth and elucidate its mechanism of action. We found that APP dimerisation can reduce neurite outgrowth by modulating extracellular and intracellular signals regulating neurite outgrowth. We determined the effect APP dimerisation has on APP neurite outgrowth by using APP dimerisation mutants, G33I and L17C (these cause decreased and increased APP dimerisation, respectively), transfected into SH-SY5Y cells. To determine if APP dimerisation utilises extracellular signalling to modulate neurite outgrowth, condition media treatment of APP dimerisation mutants was used to determine if a secreted factor was responsible for modulating neurite outgrowth. Intracellular mechanisms including APP localisation, RhoA activity and miRNA expression were investigated. The localisation of APP can affect its function therefore; immunofluorescent imaging was used to determine its localisation. RhoA GTPase is known to negatively regulate neurite outgrowth, therefore RhoA activity was determined using an ELISA based assay that was specific for activated RhoA. The Ion Torrent Next Generation Sequencing system was also used to determine the differential expression of miRNA in the APP dimerisation mutants and these were confirmed by qRT-PCR. APP-L17C mutants inhibit neurite outgrowth by inhibiting the secretion of a neurite outgrowth promoting factor as APPwt condition media treatment rescues neurite outgrowth. APP dimerisation also caused perinuclear APP aggregates which colocalised within the endoplasmic reticulum. RhoA activity is increased in the APP-L17C mutant, and treatment with condition media decreases RhoA activity which correlated with neurite outgrowth. APP dimerisation also affects several miRNA expressions. The miR-125a, miR-135b, miR-34a species, which have a known role to play in the regulation of neuritogenesis, were down regulated and transduction of an miR-34a restored neurite outgrowth back to wild type levels. In conclusion, APP dimerisation reduces neurite outgrowth and can mediate its effects by inhibiting a secreted factor, modulating APP localisation, increasing RhoA activity and modulating the expression of certain miRNAs involved in neurite outgrowth.

Subjects/Keywords: Amyloid Precursor Protein; dimerisation; neurite outgrowth

14 more images…

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Luu, L. (2017). Defining the function of Amyloid Precursor Protein dimerisation in neuritogenesis. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/194187

Chicago Manual of Style (16^th Edition):

Luu, Luan. “Defining the function of Amyloid Precursor Protein dimerisation in neuritogenesis.” 2017. Doctoral Dissertation, University of Melbourne. Accessed April 10, 2021. http://hdl.handle.net/11343/194187.

MLA Handbook (7^th Edition):

Luu, Luan. “Defining the function of Amyloid Precursor Protein dimerisation in neuritogenesis.” 2017. Web. 10 Apr 2021.

Vancouver:

Luu L. Defining the function of Amyloid Precursor Protein dimerisation in neuritogenesis. [Internet] [Doctoral dissertation]. University of Melbourne; 2017. [cited 2021 Apr 10]. Available from: http://hdl.handle.net/11343/194187.

Council of Science Editors:

Luu L. Defining the function of Amyloid Precursor Protein dimerisation in neuritogenesis. [Doctoral Dissertation]. University of Melbourne; 2017. Available from: http://hdl.handle.net/11343/194187

Drexel University

5. Nguyen, Phuong Thi Tam. Phytosterol Cyclopamine Rescues Structural and Behavioral Deficits in a Drosophila model of Alzheimer's Disease.

Degree: 2017, Drexel University

URL: http://hdl.handle.net/1860/idea:7473

►

The average person spends several hours a day behind the wheel of their vehicles, which are usually equipped with on-board computers capable of collecting real-time… (more)

Subjects/Keywords: Biology; Alzheimer's disease; Drosophila; Amyloid beta-protein; Amyloid beta-protein precursor

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Nguyen, P. T. T. (2017). Phytosterol Cyclopamine Rescues Structural and Behavioral Deficits in a Drosophila model of Alzheimer's Disease. (Thesis). Drexel University. Retrieved from http://hdl.handle.net/1860/idea:7473

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Nguyen, Phuong Thi Tam. “Phytosterol Cyclopamine Rescues Structural and Behavioral Deficits in a Drosophila model of Alzheimer's Disease.” 2017. Thesis, Drexel University. Accessed April 10, 2021. http://hdl.handle.net/1860/idea:7473.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Nguyen, Phuong Thi Tam. “Phytosterol Cyclopamine Rescues Structural and Behavioral Deficits in a Drosophila model of Alzheimer's Disease.” 2017. Web. 10 Apr 2021.

Vancouver:

Nguyen PTT. Phytosterol Cyclopamine Rescues Structural and Behavioral Deficits in a Drosophila model of Alzheimer's Disease. [Internet] [Thesis]. Drexel University; 2017. [cited 2021 Apr 10]. Available from: http://hdl.handle.net/1860/idea:7473.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Nguyen PTT. Phytosterol Cyclopamine Rescues Structural and Behavioral Deficits in a Drosophila model of Alzheimer's Disease. [Thesis]. Drexel University; 2017. Available from: http://hdl.handle.net/1860/idea:7473

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

NSYSU

6. Li, Yu-Ru. To Explore Î²-Amyloid Induced Oxidative DNA Damage and Repair in Rat Primary Cortical Neurons.

Degree: Master, Biological Sciences, 2016, NSYSU

URL: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-1103115-165537

► Alzheimer's disease (AD) is one of the common form of age-related neurodegenerative diseases and the leading cause of senile dementia. In the beta-amyloid (AÎ²) cascade… (more)

Subjects/Keywords: Î²-amyloid; Amyloid precursor protein; Alzheimer's disease; DNA repair; Neurotoxicity

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Li, Y. (2016). To Explore Î²-Amyloid Induced Oxidative DNA Damage and Repair in Rat Primary Cortical Neurons. (Thesis). NSYSU. Retrieved from http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-1103115-165537

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Li, Yu-Ru. “To Explore Î²-Amyloid Induced Oxidative DNA Damage and Repair in Rat Primary Cortical Neurons.” 2016. Thesis, NSYSU. Accessed April 10, 2021. http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-1103115-165537.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Li, Yu-Ru. “To Explore Î²-Amyloid Induced Oxidative DNA Damage and Repair in Rat Primary Cortical Neurons.” 2016. Web. 10 Apr 2021.

Vancouver:

Li Y. To Explore Î²-Amyloid Induced Oxidative DNA Damage and Repair in Rat Primary Cortical Neurons. [Internet] [Thesis]. NSYSU; 2016. [cited 2021 Apr 10]. Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-1103115-165537.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Li Y. To Explore Î²-Amyloid Induced Oxidative DNA Damage and Repair in Rat Primary Cortical Neurons. [Thesis]. NSYSU; 2016. Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-1103115-165537

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Manchester

7. Andrew, Robert. Differential Proteolysis of the Amyloid Precursor Protein Isoforms: The Role of Cellular Location and Protein-Protein Interactions.

Degree: 2015, University of Manchester

URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:280080

► Dementia, the most common cause of which is Alzheimer’s disease (AD), currently affects 850,000 people in the UK, a figure set to rise to over… (more)

▼ Dementia, the most common cause of which is Alzheimer’s disease (AD), currently affects 850,000 people in the UK, a figure set to rise to over 1 million by 2025. There is currently no disease modifying therapy available to slow or halt this progressive disease. Current understanding of AD implicates the neurotoxic amyloid-β (Aβ) peptide as the primary initiator in a cascade of events leading to the neuronal cell death and brain atrophy associated with the disease. Therefore, inhibiting the production or enhancing the clearance of Aβ within the brain has become a major target for the production of disease modifying therapeutics. Aβ is produced by brain cells through the sequential proteolytic cleavage of a larger transmembrane protein known as the amyloid precursor protein (APP) by β- and γ-secretases. Several aspects of APP physiology can influence its proteolysis, and thus Aβ production, including the isoform of APP which is expressed, its trafficking and subcellular location and its physical interactions with other proteins in the cellular environment. Here we have investigated the influence of subcellular trafficking and location and protein-protein interactions on the differential proteolysis of two APP isoforms, APP695 and APP751 in a neuroblastoma cell line. We have shown that APP751 undergoes less amyloidogenic proteolysis than APP695 and that retention within the early secretory pathway may contribute to this difference. APP751 shows higher co-localisation to the trans-Golgi network than APP695 in immunofluorescence microscopy studies, while addition of a mutation which causes APP proteolysis in the secretory pathway reduces the large difference in amyloidogenic proteolysis of these two isoforms. Targeting APP endocytosis from the cell surface, thought to be a key determinant in Aβ generation, effects APP isoform proteolysis and Aβ production to a similar extent in both the APP isoforms suggesting differences in proteolysis occur before this trafficking event. We also show by immunoblot analysis that the APP isoforms may be differentially cleaved by proteases other than β- and γ-secretase to produce recently identified proteolytic fragments. Using a liquid chromatography – tandem mass spectrometry approach coupled to prior stable isotope labelling of amino acids in cell culture (SILAC), we have identified the interactomes of the two APP isoforms in our model system. Gene ontology analysis identified enrichment of nuclear and mitochondrial proteins specifically in the APP695 interactome. Using siRNA mediated protein knockdown, we have shown interactions with Fe65 and ataxin-10 specifically influence Aβ generation from the APP695 isoform. Fe65 alters proteolysis at the rate limiting β-secretase cleavage step, while ataxin-10 alters proteolysis by γ-secretase. Interaction with growth-associated protein 43 specifically influences Aβ generation from the APP751 isoform, altering proteolysis at the γ-secretase step. Finally we have shown that recently discovered familial AD-linked mutation and protective mutation… Advisors/Committee Members: PICKERING-BROWN, STUART SM, Pickering-Brown, Stuart, Hooper, Nigel.

Subjects/Keywords: Alzheimers disease; Amyloid precursor protein; Amyloid-beta; interactome; Proteolysis

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Andrew, R. (2015). Differential Proteolysis of the Amyloid Precursor Protein Isoforms: The Role of Cellular Location and Protein-Protein Interactions. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:280080

Chicago Manual of Style (16^th Edition):

Andrew, Robert. “Differential Proteolysis of the Amyloid Precursor Protein Isoforms: The Role of Cellular Location and Protein-Protein Interactions.” 2015. Doctoral Dissertation, University of Manchester. Accessed April 10, 2021. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:280080.

MLA Handbook (7^th Edition):

Andrew, Robert. “Differential Proteolysis of the Amyloid Precursor Protein Isoforms: The Role of Cellular Location and Protein-Protein Interactions.” 2015. Web. 10 Apr 2021.

Vancouver:

Andrew R. Differential Proteolysis of the Amyloid Precursor Protein Isoforms: The Role of Cellular Location and Protein-Protein Interactions. [Internet] [Doctoral dissertation]. University of Manchester; 2015. [cited 2021 Apr 10]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:280080.

Council of Science Editors:

Andrew R. Differential Proteolysis of the Amyloid Precursor Protein Isoforms: The Role of Cellular Location and Protein-Protein Interactions. [Doctoral Dissertation]. University of Manchester; 2015. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:280080

8. Kirouac, Lisa. The Concerted Regulation of Intracellular Signaling by Amyloid Precursor Protein and Aβ Peptide.

Degree: 2016, University of South Florida

URL: https://scholarcommons.usf.edu/etd/6278

► It is widely accepted that A-beta (Aβ) generated from amyloid precursor protein (APP) oligomerizes and fibrillizes to form neuritic plaques in the Alzheimer’s disease (AD)… (more)

▼ It is widely accepted that A-beta (Aβ) generated from amyloid precursor protein (APP) oligomerizes and fibrillizes to form neuritic plaques in the Alzheimer’s disease (AD) brain, yet little is known about the contribution of APP preceding AD pathogenesis. Our data presented here suggest that APP has a functional role in cell cycle regulation and proliferation. First, we demonstrat that APP is pathologically phosphorylated at Thr668 and that P-APP localizes to the centrosomes. Furthermore, P-APP is proteolytically processed in a cell cycle -dependent manner to generate its pathogenic metabolites. Using Stable Isotope Labeling by Amino Acids in Culture (SILAC) and mass spectrometry analyses, we also show that expression of APP results in the expression of proliferation-associated proteins and the phosphorylation of proteins associated with cell cycle regulation and transcription. Here, we demonstrate that APP expression and oligomeric Aβ42 elicit Ras/ERK signaling cascade and glycogen synthase kinase3 (GSK3) activation. Both ERK and GSK3 are known to induce hyperphosphorylation of tau and of APP at Thr668, and our findings suggest that aberrant signaling by APP facilitates these events. Supporting this notion, analysis of human brain samples show increased expression of Ras, activation of GSK3 and phosphorylation of APP and tau, which correlate with Aβ levels in the AD brains. Furthermore, treatment of primary rat neurons with Aβ recapitulate these events and show enhanced Ras-ERK signaling, GSK3 activation, upregulation of cyclin D1, and phosphorylation of APP and tau. The finding that Aβ induces Thr668 phosphorylation on APP, which we show enhances APP proteolysis and Aβ generation, denotes a vicious feed-forward mechanism by which APP and Aβ promote tau hyperphosphorylation and neurodegeneration in AD. Based on these results we hypothesize that aberrant proliferative signaling by APP plays a fundamental role in AD neurodegeneration and an inhibition of this would impede the mitotic catastrophe and neurodegeneration observed in AD.

Subjects/Keywords: Alzheimer’s disease; amyloid-beta; amyloid precursor protein; mitosis; proliferation; Neurosciences

11 more images…

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Kirouac, L. (2016). The Concerted Regulation of Intracellular Signaling by Amyloid Precursor Protein and Aβ Peptide. (Thesis). University of South Florida. Retrieved from https://scholarcommons.usf.edu/etd/6278

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Kirouac, Lisa. “The Concerted Regulation of Intracellular Signaling by Amyloid Precursor Protein and Aβ Peptide.” 2016. Thesis, University of South Florida. Accessed April 10, 2021. https://scholarcommons.usf.edu/etd/6278.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Kirouac, Lisa. “The Concerted Regulation of Intracellular Signaling by Amyloid Precursor Protein and Aβ Peptide.” 2016. Web. 10 Apr 2021.

Vancouver:

Kirouac L. The Concerted Regulation of Intracellular Signaling by Amyloid Precursor Protein and Aβ Peptide. [Internet] [Thesis]. University of South Florida; 2016. [cited 2021 Apr 10]. Available from: https://scholarcommons.usf.edu/etd/6278.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Kirouac L. The Concerted Regulation of Intracellular Signaling by Amyloid Precursor Protein and Aβ Peptide. [Thesis]. University of South Florida; 2016. Available from: https://scholarcommons.usf.edu/etd/6278

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Duke University

9. Christianson, Melissa Gottron. Amyloid Precursor Protein-Dependent and -Independent Mechanisms in Hypoxia-Induced Axonopathy .

Degree: 2012, Duke University

URL: http://hdl.handle.net/10161/5427

► Hypoxia is a profound stressor of the central nervous system implicated in numerous neurodegenerative diseases. While it is increasingly evident that the early effects… (more)

Subjects/Keywords: Neurosciences; Alzheimer's disease; Amyloid Beta; Amyloid Precursor Protein; Axon; Hypoxia; Neurodegeneration

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Christianson, M. G. (2012). Amyloid Precursor Protein-Dependent and -Independent Mechanisms in Hypoxia-Induced Axonopathy . (Thesis). Duke University. Retrieved from http://hdl.handle.net/10161/5427

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Christianson, Melissa Gottron. “Amyloid Precursor Protein-Dependent and -Independent Mechanisms in Hypoxia-Induced Axonopathy .” 2012. Thesis, Duke University. Accessed April 10, 2021. http://hdl.handle.net/10161/5427.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Christianson, Melissa Gottron. “Amyloid Precursor Protein-Dependent and -Independent Mechanisms in Hypoxia-Induced Axonopathy .” 2012. Web. 10 Apr 2021.

Vancouver:

Christianson MG. Amyloid Precursor Protein-Dependent and -Independent Mechanisms in Hypoxia-Induced Axonopathy . [Internet] [Thesis]. Duke University; 2012. [cited 2021 Apr 10]. Available from: http://hdl.handle.net/10161/5427.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Christianson MG. Amyloid Precursor Protein-Dependent and -Independent Mechanisms in Hypoxia-Induced Axonopathy . [Thesis]. Duke University; 2012. Available from: http://hdl.handle.net/10161/5427

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Manchester

10. Andrew, Robert. Differential proteolysis of the amyloid precursor protein isoforms : the role of cellular location and protein-protein interactions.

Degree: PhD, 2015, University of Manchester

URL: https://www.research.manchester.ac.uk/portal/en/theses/differential-proteolysis-of-the-amyloid-precursor-protein-isoforms-the-role-of-cellular-location-and-proteinprotein-interactions(5390e8fa-fc5e-4357-8109-cb2bb1c49212).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.764346

► Dementia, the most common cause of which is Alzheimer's disease (AD), currently affects 850,000 people in the UK, a figure set to rise to over… (more)

▼ Dementia, the most common cause of which is Alzheimer's disease (AD), currently affects 850,000 people in the UK, a figure set to rise to over 1 million by 2025. There is currently no disease modifying therapy available to slow or halt this progressive disease. Current understanding of AD implicates the neurotoxic amyloid-β (Aβ) peptide as the primary initiator in a cascade of events leading to the neuronal cell death and brain atrophy associated with the disease. Therefore, inhibiting the production or enhancing the clearance of Aβ within the brain has become a major target for the production of disease modifying therapeutics. Aβ is produced by brain cells through the sequential proteolytic cleavage of a larger transmembrane protein known as the amyloid precursor protein (APP) by β- and γ-secretases. Several aspects of APP physiology can influence its proteolysis, and thus Aβ production, including the isoform of APP which is expressed, its trafficking and subcellular location and its physical interactions with other proteins in the cellular environment. Here we have investigated the influence of subcellular trafficking and location and protein-protein interactions on the differential proteolysis of two APP isoforms, APP695 and APP751 in a neuroblastoma cell line. We have shown that APP751 undergoes less amyloidogenic proteolysis than APP695 and that retention within the early secretory pathway may contribute to this difference. APP751 shows higher co-localisation to the trans-Golgi network than APP695 in immunofluorescence microscopy studies, while addition of a mutation which causes APP proteolysis in the secretory pathway reduces the large difference in amyloidogenic proteolysis of these two isoforms. Targeting APP endocytosis from the cell surface, thought to be a key determinant in Aβ generation, effects APP isoform proteolysis and Aβ production to a similar extent in both the APP isoforms suggesting differences in proteolysis occur before this trafficking event. We also show by immunoblot analysis that the APP isoforms may be differentially cleaved by proteases other than β- and γ-secretase to produce recently identified proteolytic fragments. Using a liquid chromatography - tandem mass spectrometry approach coupled to prior stable isotope labelling of amino acids in cell culture (SILAC), we have identified the interactomes of the two APP isoforms in our model system. Gene ontology analysis identified enrichment of nuclear and mitochondrial proteins specifically in the APP695 interactome. Using siRNA mediated protein knockdown, we have shown interactions with Fe65 and ataxin-10 specifically influence Aβ generation from the APP695 isoform. Fe65 alters proteolysis at the rate limiting β-secretase cleavage step, while ataxin-10 alters proteolysis by γ-secretase. Interaction with growth-associated protein 43 specifically influences Aβ generation from the APP751 isoform, altering proteolysis at the γ-secretase step. Finally we have shown that recently discovered familial AD-linked mutation and protective mutation…

Subjects/Keywords: 616.8; Alzheimers disease; Amyloid precursor protein; Amyloid-beta; interactome; Proteolysis

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Andrew, R. (2015). Differential proteolysis of the amyloid precursor protein isoforms : the role of cellular location and protein-protein interactions. (Doctoral Dissertation). University of Manchester. Retrieved from https://www.research.manchester.ac.uk/portal/en/theses/differential-proteolysis-of-the-amyloid-precursor-protein-isoforms-the-role-of-cellular-location-and-proteinprotein-interactions(5390e8fa-fc5e-4357-8109-cb2bb1c49212).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.764346

Chicago Manual of Style (16^th Edition):

Andrew, Robert. “Differential proteolysis of the amyloid precursor protein isoforms : the role of cellular location and protein-protein interactions.” 2015. Doctoral Dissertation, University of Manchester. Accessed April 10, 2021. https://www.research.manchester.ac.uk/portal/en/theses/differential-proteolysis-of-the-amyloid-precursor-protein-isoforms-the-role-of-cellular-location-and-proteinprotein-interactions(5390e8fa-fc5e-4357-8109-cb2bb1c49212).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.764346.

MLA Handbook (7^th Edition):

Andrew, Robert. “Differential proteolysis of the amyloid precursor protein isoforms : the role of cellular location and protein-protein interactions.” 2015. Web. 10 Apr 2021.

Vancouver:

Andrew R. Differential proteolysis of the amyloid precursor protein isoforms : the role of cellular location and protein-protein interactions. [Internet] [Doctoral dissertation]. University of Manchester; 2015. [cited 2021 Apr 10]. Available from: https://www.research.manchester.ac.uk/portal/en/theses/differential-proteolysis-of-the-amyloid-precursor-protein-isoforms-the-role-of-cellular-location-and-proteinprotein-interactions(5390e8fa-fc5e-4357-8109-cb2bb1c49212).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.764346.

Council of Science Editors:

Andrew R. Differential proteolysis of the amyloid precursor protein isoforms : the role of cellular location and protein-protein interactions. [Doctoral Dissertation]. University of Manchester; 2015. Available from: https://www.research.manchester.ac.uk/portal/en/theses/differential-proteolysis-of-the-amyloid-precursor-protein-isoforms-the-role-of-cellular-location-and-proteinprotein-interactions(5390e8fa-fc5e-4357-8109-cb2bb1c49212).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.764346

NSYSU

11. Chen, Chueh-Tan. The Possible Role of Neuron Autophagy on Amyloidogenesis Disorderswith Lead Exposure.

Degree: Master, Biological Sciences, 2012, NSYSU

URL: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0216112-112117

► Lead (Pb) is one of the most well known toxic heavy metals in human beings and animals, which leads to toxic neurological disorders, cognitive problems,… (more)

▼ Lead (Pb) is one of the most well known toxic heavy metals in human beings and animals, which leads to toxic neurological disorders, cognitive problems, learning and memory disabilities. Epidemiological studies revealed that chronic lead exposure is one of the environmental risk factors which may cause Alzheimerâs Disease, which were speculated for the observation of cellular necrosis, apoptosis, and Î²-amyloid deposition frequently occuring altogether after chronic lead exposure. Recent studies have shown that the Î²-amyloid formed during autophagic turnover of APP-rich organelles supplied by both autophagy and endocytosis. Therefore, we will conduct the new perspective for studying the possible role of autophagy on amyloidogensis disorders after lead exposure. SH-SY5Y human neuroblastoma cells, used in this study, were differentiated to a neuronal phenotype by retinoic acid (RA) to the culture medium at 10 Î¼M for 1, 2, 3 and 4 days. Doses of lead acetate with of lead acetate were 5 Î¼M and applied to the neuronal culture and then cell viability measurement by MTT assay. The apoptotic effect of non-differentiation and differentiation neuroblastoma cells after lead exposure was determined by cleaved DNA fragments. Furthermore, APP, intracellular AÎ²1-40 and AÎ²1-42 expression were quantified by Real-time PCR and ELISA, respectively. The autophagy process and variation of total and phosphorylated mammalian target of rapamycin (mTOR) forms were determined after lead exposure in non-differentiation and differentiation neuroblastoma cells by western blot. The results indicate that lead exposure enhances autophagy response in both non-differentiation and differentiation SH-SY5Y cells, which might cause neuronal apoptosis associated with Î²-amyloidgenesis. Otherwise, lead exposure resulted in the inhibition of mTOR signaling, which correlated with the autophagic process. Besides, in our studies, non-differentiated cells exhibited more toxic vulnerability than RA induced differentiated neuron is congruous to previous finding that lead exposure during fetal development might be a potential risk factor for AD in the adulthood. Advisors/Committee Members: Chen,Tsan-Ju (chair), Cheng, Jiin-Tsuey (committee member), Tai,Ming-Hong (chair), Chen, Shun-Sheng (committee member).

Subjects/Keywords: Alzheimerâs Disease; amyloid precursor protein; autophagy; amyloidogensis disorders; apoptosis; Î²-amyloid protein; lead exposure

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Chen, C. (2012). The Possible Role of Neuron Autophagy on Amyloidogenesis Disorderswith Lead Exposure. (Thesis). NSYSU. Retrieved from http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0216112-112117

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Chen, Chueh-Tan. “The Possible Role of Neuron Autophagy on Amyloidogenesis Disorderswith Lead Exposure.” 2012. Thesis, NSYSU. Accessed April 10, 2021. http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0216112-112117.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Chen, Chueh-Tan. “The Possible Role of Neuron Autophagy on Amyloidogenesis Disorderswith Lead Exposure.” 2012. Web. 10 Apr 2021.

Vancouver:

Chen C. The Possible Role of Neuron Autophagy on Amyloidogenesis Disorderswith Lead Exposure. [Internet] [Thesis]. NSYSU; 2012. [cited 2021 Apr 10]. Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0216112-112117.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Chen C. The Possible Role of Neuron Autophagy on Amyloidogenesis Disorderswith Lead Exposure. [Thesis]. NSYSU; 2012. Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0216112-112117

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Vanderbilt University

12. DelBove, Claire Elise. Visualizing APP trafficking and processing reveals its functional relationship with neuronal membrane cholesterol.

Degree: PhD, Pharmacology, 2018, Vanderbilt University

URL: http://hdl.handle.net/1803/13502

► Amyloid precursor protein (APP) is a type I transmembrane protein and has been studied extensively due to its relevance to Alzheimer’s disease. However, its subcellular… (more)

Subjects/Keywords: Alzheimers disease; choleserol; protein trafficking; amyloid precursor protein

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

DelBove, C. E. (2018). Visualizing APP trafficking and processing reveals its functional relationship with neuronal membrane cholesterol. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/13502

Chicago Manual of Style (16^th Edition):

DelBove, Claire Elise. “Visualizing APP trafficking and processing reveals its functional relationship with neuronal membrane cholesterol.” 2018. Doctoral Dissertation, Vanderbilt University. Accessed April 10, 2021. http://hdl.handle.net/1803/13502.

MLA Handbook (7^th Edition):

DelBove, Claire Elise. “Visualizing APP trafficking and processing reveals its functional relationship with neuronal membrane cholesterol.” 2018. Web. 10 Apr 2021.

Vancouver:

DelBove CE. Visualizing APP trafficking and processing reveals its functional relationship with neuronal membrane cholesterol. [Internet] [Doctoral dissertation]. Vanderbilt University; 2018. [cited 2021 Apr 10]. Available from: http://hdl.handle.net/1803/13502.

Council of Science Editors:

DelBove CE. Visualizing APP trafficking and processing reveals its functional relationship with neuronal membrane cholesterol. [Doctoral Dissertation]. Vanderbilt University; 2018. Available from: http://hdl.handle.net/1803/13502

University of Melbourne

13. Truong, Phan Hong. Investigating the role of Amyloid Precursor-Like Protein 2 in Motor Neurone Disease.

Degree: 2019, University of Melbourne

URL: http://hdl.handle.net/11343/227648

► Motor neurone disease (MND) is a fatal human neurodegenerative disorder. The most common form of MND is amyotrophic lateral sclerosis (ALS). MND is characterised by… (more)

▼ Motor neurone disease (MND) is a fatal human neurodegenerative disorder. The most common form of MND is amyotrophic lateral sclerosis (ALS). MND is characterised by the progressive destruction of motor neurons in the central nervous system which causes muscle weakness, muscle atrophy, paralysis and ultimately death. The sporadic forms of the disease account for the majority of patients, and 5-10% of MND cases are inherited (familial MND) (Marin et al., 2017). Both sporadic and familial MND share similar clinical and pathological features, suggesting common molecular mechanisms of degeneration. Among the familial MND patients approximately 20% possess a mutation in the SOD1 gene encoding for the enzyme Cu/Zn superoxide dismutase (Rosen et al., 1993). There are more than 170 different SOD1 gene mutations described, and the majority are missense substitutions resulting in a toxic gain of enzyme function (http://alsod.iop.kcl.ac.uk/). Transgenic mouse models over-expressing mutant forms of the human SOD1 gene replicate key pathological symptoms seen in MND patients and are widely used to study MND. Despite progress in deciphering the molecular mechanisms of this disease, the cause and modulation of MND remains unclear. The Amyloid Precursor Protein (APP), is well-known for its association with Alzheimer's Disease, and it has been shown to be a modulator of MND. APP protein expression levels were increased in the spinal cords from MND patients as well as in SOD1 transgenic mice at symptomatic stage of the disease (Koistinen et al., 2006; Rabinovich-Toidman et al., 2015). The resultant SOD1-G93A:APP-/- mice from the cross breeding between APP homozygous deletion and SOD1-G93A transgenic mice (overexpress human SOD1 gene with G93A familial mutation) showed significant decrease in MND pathogenesis and reduced disease progression (Bryson et al., 2012). The SOD1-G93A:APP-/- mice also displayed significantly ameliorated muscle contractility, improved neuromuscular junction innervation and decreased motor neuron loss. Taken together these findings suggest an important role for APP in MND pathophysiology. APP is part of a gene family that includes the amyloid precursor-like protein 1 (APLP1) and amyloid precursor-like protein 2 (APLP2) genes. To understand if other APP-family members modulated MND we investigated the role of APLP2 in the SOD1-G37R transgenic mouse model. We found a significant sex-dependent increase in the expression of APLP2 protein in the spinal cord of the SOD1-G37R mice. To test if APLP2 gene expression can modulate disease outcomes in MND we crossed the SOD1-G37R and APLP2 knockout (KO) mice to generate the SOD1:APLP2+/- and SOD1:APLP2-/- lines. We found the lack of APLP2 expression improved motor performance and extend survival in a sex-dependent manner. The molecular basis for APLP2’s actions identified effects on muscle physiology and synaptic function at the neuromuscular junction. Taken together, our novel results demonstrate there are sex-dependent differences in the SOD1 mouse model, and…

Subjects/Keywords: amyloid precursor – like protein 2; motor neurone disease; amyloid precursor protein; SOD1-G37R; superoxide dismutase; motor neurons; sex differences; knockout; transgenic

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Truong, P. H. (2019). Investigating the role of Amyloid Precursor-Like Protein 2 in Motor Neurone Disease. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/227648

Chicago Manual of Style (16^th Edition):

Truong, Phan Hong. “Investigating the role of Amyloid Precursor-Like Protein 2 in Motor Neurone Disease.” 2019. Doctoral Dissertation, University of Melbourne. Accessed April 10, 2021. http://hdl.handle.net/11343/227648.

MLA Handbook (7^th Edition):

Truong, Phan Hong. “Investigating the role of Amyloid Precursor-Like Protein 2 in Motor Neurone Disease.” 2019. Web. 10 Apr 2021.

Vancouver:

Truong PH. Investigating the role of Amyloid Precursor-Like Protein 2 in Motor Neurone Disease. [Internet] [Doctoral dissertation]. University of Melbourne; 2019. [cited 2021 Apr 10]. Available from: http://hdl.handle.net/11343/227648.

Council of Science Editors:

Truong PH. Investigating the role of Amyloid Precursor-Like Protein 2 in Motor Neurone Disease. [Doctoral Dissertation]. University of Melbourne; 2019. Available from: http://hdl.handle.net/11343/227648

University of California – San Diego

14. Fong, Lauren Kristen. Elucidating Amyloid Precursor Protein Function in Human Astrocytes Derived from Pluripotent Stem Cells.

Degree: Biomedical Sciences, 2016, University of California – San Diego

URL: http://www.escholarship.org/uc/item/5740p2b0

► Successful development of effective therapeutics for Alzheimer’s disease (AD) requires a deep understanding of the mechanisms of disease pathogenesis. Recent human induced pluripotent stem cell… (more)

▼ Successful development of effective therapeutics for Alzheimer’s disease (AD) requires a deep understanding of the mechanisms of disease pathogenesis. Recent human induced pluripotent stem cell (hiPSC)-derived models have shown it is possible to recapitulate the complex genetic diversity of a patient and more completely model AD pathology. While most work has focused on neuronal AD phenotypes, there is mounting evidence that failure to regulate cholesterol homeostasis by neighboring nonneuronal support cells may be involved in AD pathogenesis. Amyloid precursor protein (APP) or multiple fragments generated by APP proteolytic processing have previously been implicated in the regulation of cholesterol metabolism. However, the physiological function of APP in regulating lipoprotein homeostasis in astrocytes, which are responsible for the brain’s de novo cholesterol biosynthesis and regulation, remains unclear. To address this, we independently validated and characterized a novel in vitro differentiation protocol to generate human astrocytes from hiPSC. We found that cells derived by this method recapitulated native astrocytes in their form and function. We also utilized CRISPR/Cas9 genome editing to generate isogenic APP knockout (KO) hiPSCs. We found that APP KO astrocytes have reduced cholesterol, elevated levels of sterol regulatory element-binding protein (SREBP)-target gene transcripts, and increased low-density lipoprotein (LDL) receptor protein, all downstream consequences of reduced lipoprotein endocytosis. To elucidate which APP fragments regulate cholesterol homeostasis and examine whether familial AD mutations in APP affect lipoprotein metabolism, we analyzed an isogenic allelic series using the APP Swedish and APP V717F mutations. Only astrocytes homozygous for the APP Swedish (APPSwe/Swe) mutation, which had reduced full-length APP (FL APP) due to aggressive beta-secretase cleavage, recapitulated the APP KO phenotypes. Further, astrocytic internalization of amyloid-beta (A-beta), another ligand of LDL receptors, was impaired in APP KO and APPSwe/Swe astrocytes. Given that FL APP is known to bind to multiple LDL receptors, we propose that FL APP acts as a co-receptor for known LDL receptor ligands and is required for proper cholesterol homeostasis and A-beta clearance in human astrocytes.

Subjects/Keywords: Biology; Neurosciences; Amyloid-beta; Amyloid Precursor Protein; Astrocyte; Cholesterol; Lipoprotein; Stem Cell

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Fong, L. K. (2016). Elucidating Amyloid Precursor Protein Function in Human Astrocytes Derived from Pluripotent Stem Cells. (Thesis). University of California – San Diego. Retrieved from http://www.escholarship.org/uc/item/5740p2b0

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Fong, Lauren Kristen. “Elucidating Amyloid Precursor Protein Function in Human Astrocytes Derived from Pluripotent Stem Cells.” 2016. Thesis, University of California – San Diego. Accessed April 10, 2021. http://www.escholarship.org/uc/item/5740p2b0.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Fong, Lauren Kristen. “Elucidating Amyloid Precursor Protein Function in Human Astrocytes Derived from Pluripotent Stem Cells.” 2016. Web. 10 Apr 2021.

Vancouver:

Fong LK. Elucidating Amyloid Precursor Protein Function in Human Astrocytes Derived from Pluripotent Stem Cells. [Internet] [Thesis]. University of California – San Diego; 2016. [cited 2021 Apr 10]. Available from: http://www.escholarship.org/uc/item/5740p2b0.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Fong LK. Elucidating Amyloid Precursor Protein Function in Human Astrocytes Derived from Pluripotent Stem Cells. [Thesis]. University of California – San Diego; 2016. Available from: http://www.escholarship.org/uc/item/5740p2b0

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

15. S. Therin. USE OF A CELL PERMEABLE PEPTIDE TO MODULATE ADAM10 SYNAPTIC LOCALIZATION AND ACTIVITY IN A MOUSE MODEL OF ALZHEIMER'S DISEASE.

Degree: 2019, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/649095

► Alzheimer’s disease (AD) is characterized by the aggregation of amyloid beta peptide (Aβ). Aβ derives from the amyloid precursor protein (APP), which can undergo two… (more)

▼ Alzheimer’s disease (AD) is characterized by the aggregation of amyloid beta peptide (Aβ). Aβ derives from the amyloid precursor protein (APP), which can undergo two mutually exclusive pathways. The amyloidogenic pathway involves BACE and γ-secretase activities and leads to Aβ formation. While, the non-amyloidogenic pathway involves ADAM10, a disintegrin and metalloproteinase 10, which cleaves APP within the domain corresponding to Aβ, thus precluding Aβ production. Recently, we identified a new ADAM10 binding partner, named AP2, which is responsible for ADAM10 internalization, therefore affecting its activity. Interestingly, ADAM10/AP2 interaction is significantly increased in AD patients' brain compared to healthy control subjects, suggesting a role of ADAM10/AP2 in AD pathogenesis. In this framework, we have recently developed a cell permeable peptide (named PEP3) capable of interfering with ADAM10/AP2 association. The intraperitoneal administration of this CPP to a mouse model of AD for two weeks is safe and effective in impairing ADAM10 endocytosis and, thereby, in increasing ADAM10 synaptic localization. At late stages of disease, the PEP3 administration is able to change biochemical parameters, as Aβ levels and the molecular composition of the synapses without ameliorating the cognitive deficits of these mice. On the other hand, at early stage of the pathology the 14-days administration of the PEP3 rescues the cognitive impairment of the AD mice. Further investigations revealed that the synaptic levels of the NMDA receptor subunit GluN2A are increased upon the treatment and that previously observed shrinkage and dendritic spine loss in AD mice were improved after CPP treatment. These results are mediated by an increase in endogenous sAPPα. These positive results point to ADAM10 internalization as a potential target mechanism for the development of an effective AD therapy. Advisors/Committee Members: tutor: M. Di Luca, co-tutor: E. Marcello, coordinator: A. L. Catapano, DILUCA, MONICA MARIA GRAZIA, CATAPANO, ALBERICO LUIGI.

Subjects/Keywords: Alzheimer's disease; ADAM10; Amyloid precursor protein; Amyloid beta; APP/PS1 mouse; Settore BIO/14 - Farmacologia

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Therin, S. (2019). USE OF A CELL PERMEABLE PEPTIDE TO MODULATE ADAM10 SYNAPTIC LOCALIZATION AND ACTIVITY IN A MOUSE MODEL OF ALZHEIMER'S DISEASE. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/649095

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Therin, S.. “USE OF A CELL PERMEABLE PEPTIDE TO MODULATE ADAM10 SYNAPTIC LOCALIZATION AND ACTIVITY IN A MOUSE MODEL OF ALZHEIMER'S DISEASE.” 2019. Thesis, Università degli Studi di Milano. Accessed April 10, 2021. http://hdl.handle.net/2434/649095.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Therin, S.. “USE OF A CELL PERMEABLE PEPTIDE TO MODULATE ADAM10 SYNAPTIC LOCALIZATION AND ACTIVITY IN A MOUSE MODEL OF ALZHEIMER'S DISEASE.” 2019. Web. 10 Apr 2021.

Vancouver:

Therin S. USE OF A CELL PERMEABLE PEPTIDE TO MODULATE ADAM10 SYNAPTIC LOCALIZATION AND ACTIVITY IN A MOUSE MODEL OF ALZHEIMER'S DISEASE. [Internet] [Thesis]. Università degli Studi di Milano; 2019. [cited 2021 Apr 10]. Available from: http://hdl.handle.net/2434/649095.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Therin S. USE OF A CELL PERMEABLE PEPTIDE TO MODULATE ADAM10 SYNAPTIC LOCALIZATION AND ACTIVITY IN A MOUSE MODEL OF ALZHEIMER'S DISEASE. [Thesis]. Università degli Studi di Milano; 2019. Available from: http://hdl.handle.net/2434/649095

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Bath

16. Roberts, Hazel. Alpha-synuclein expression influences the processing of the amyloid precursor protein.

Degree: PhD, 2016, University of Bath

URL: https://researchportal.bath.ac.uk/en/studentthesis/alphasynuclein-expression-influences-the-processing-of-the-amyloid-precursor-protein(81175adb-7013-402d-82e6-f309a6890030).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.707587

► In certain neurodegenerative diseases such Dementia with Lewy Bodies (DLB), it is hypothesised that misfolded α-synuclein (α-syn) and β-amyloid both contribute to pathology. α-Syn and… (more)

▼ In certain neurodegenerative diseases such Dementia with Lewy Bodies (DLB), it is hypothesised that misfolded α-synuclein (α-syn) and β-amyloid both contribute to pathology. α-Syn and β-amyloid have been suggested to synergistically promote one another’s accumulation and aggregation, but the mechanisms are unknown. β-Amyloid is generated from β-/γ-secretase-mediated processing of the amyloid precursor protein (APP). This study investigated how α-syn overexpression in cells affects β-amyloid production from APP, using multiplex assays, luciferase reporter assays, and western blotting. Wildtype α-syn expression induces β-amyloid generation from APP in SH-SY5Y human neuroblastoma cells, and similar changes to APP processing occur in another neuronal cell model. Dominant-negative overexpression of α-syn mutants revealed that disrupting the N-terminal domain can increase APP amyloidogenic processing. Secretase enzymes that perform APP processing were next investigated. γ-Secretase activity, measured by a luciferase reporter, was not increased by α-syn overexpression. A higher ratio of β- to α-secretase processing was hypothesised, which led to expression and activity studies of the major β- and α-secretases, BACE1 and ADAM10 respectively. It was shown that the BACE1 protein expression is post-transcriptionally upregulated in α-syn cells, with increased APP cleavage in cells. ADAM10 protein expression is transcriptionally suppressed in wild-type α-syn cells, reducing total levels of catalytically active enzyme. However the change in ADAM10-mediated APP processing may be negligible since, critically, plasma membrane expression of ADAM10 appears to be maintained. To aid understanding of the mechanism that connects α-syn to APP processing, BACE1 expression was used in pharmacological studies of cell stress signalling. This approach revealed that in α-syn cells BACE1 lysosomal and/or proteasomal degradation may be disturbed. Additionally, BACE1 expression is induced by translational de-repression mediated by eIF2α ser-51 phosphorylation, which was increased in α-syn cells. Although preliminary, the data suggests a role for oxidative stress mediating the increased BACE1 expression in wild-type α-syn cells.

Subjects/Keywords: 616.8; alpha-synuclein; amyloid precursor protein; amyloid-beta peptide; beta-secretase; alpha-secretase

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Roberts, H. (2016). Alpha-synuclein expression influences the processing of the amyloid precursor protein. (Doctoral Dissertation). University of Bath. Retrieved from https://researchportal.bath.ac.uk/en/studentthesis/alphasynuclein-expression-influences-the-processing-of-the-amyloid-precursor-protein(81175adb-7013-402d-82e6-f309a6890030).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.707587

Chicago Manual of Style (16^th Edition):

Roberts, Hazel. “Alpha-synuclein expression influences the processing of the amyloid precursor protein.” 2016. Doctoral Dissertation, University of Bath. Accessed April 10, 2021. https://researchportal.bath.ac.uk/en/studentthesis/alphasynuclein-expression-influences-the-processing-of-the-amyloid-precursor-protein(81175adb-7013-402d-82e6-f309a6890030).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.707587.

MLA Handbook (7^th Edition):

Roberts, Hazel. “Alpha-synuclein expression influences the processing of the amyloid precursor protein.” 2016. Web. 10 Apr 2021.

Vancouver:

Roberts H. Alpha-synuclein expression influences the processing of the amyloid precursor protein. [Internet] [Doctoral dissertation]. University of Bath; 2016. [cited 2021 Apr 10]. Available from: https://researchportal.bath.ac.uk/en/studentthesis/alphasynuclein-expression-influences-the-processing-of-the-amyloid-precursor-protein(81175adb-7013-402d-82e6-f309a6890030).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.707587.

Council of Science Editors:

Roberts H. Alpha-synuclein expression influences the processing of the amyloid precursor protein. [Doctoral Dissertation]. University of Bath; 2016. Available from: https://researchportal.bath.ac.uk/en/studentthesis/alphasynuclein-expression-influences-the-processing-of-the-amyloid-precursor-protein(81175adb-7013-402d-82e6-f309a6890030).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.707587

Stony Brook University

17. Chiang, Hsueh-Chiang. Drosophila Model of Alzheimer's Disease .

Degree: 2009, Stony Brook University

URL: http://hdl.handle.net/1951/52212

Subjects/Keywords: Beta-amyloid precursor protein

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Chiang, H. (2009). Drosophila Model of Alzheimer's Disease . (Thesis). Stony Brook University. Retrieved from http://hdl.handle.net/1951/52212

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Chiang, Hsueh-Chiang. “Drosophila Model of Alzheimer's Disease .” 2009. Thesis, Stony Brook University. Accessed April 10, 2021. http://hdl.handle.net/1951/52212.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Chiang, Hsueh-Chiang. “Drosophila Model of Alzheimer's Disease .” 2009. Web. 10 Apr 2021.

Vancouver:

Chiang H. Drosophila Model of Alzheimer's Disease . [Internet] [Thesis]. Stony Brook University; 2009. [cited 2021 Apr 10]. Available from: http://hdl.handle.net/1951/52212.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Chiang H. Drosophila Model of Alzheimer's Disease . [Thesis]. Stony Brook University; 2009. Available from: http://hdl.handle.net/1951/52212

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Tasmania

18. Dawkins, E. Role of Phosphoinositides in the biology of the amyloid precursor protein.

Degree: 2014, University of Tasmania

URL: https://eprints.utas.edu.au/18274/1/front-Dawkins-thesis.pdf ; https://eprints.utas.edu.au/18274/2/Whole-Dawkins-thesis.pdf

► Alzheimer’s disease (AD) is the leading cause of dementia in the elderly. In countries with aging populations, such as Australia, the prevalence of AD is… (more)

▼ Alzheimer’s disease (AD) is the leading cause of dementia in the elderly. In countries with aging populations, such as Australia, the prevalence of AD is projected to increase substantially. AD is characterised by two distinctive pathological lesions in the brain, amyloid plaques and neurofibrillary tangles. The major component of amyloid plaques is an aggregating protein termed the betaamyloid protein (Aβ). Aβ is formed normally from a larger precursor protein, known as the beta-amyloid precursor protein (APP). Although APP is centrally involved in the pathogenesis of Alzheimer’s disease and the production of Aβ, relatively little is known about its normal function. Deciphering the function of APP in the brain may be essential for the development of effective AD therapeutics. APP is a type I transmembrane glycoprotein that can be proteolytically processed by α, β- and γ-secretases to produce a number of secreted ectodomain fragments termed sAPPβ, sAPPα, Aβ and p3. Many studies have suggested that sAPPα may act in the maintenance and development of the central nervous system, by acting as a paracrine factor. In vitro, sAPPα has been reported to modulate the proliferation and differentiation of a variety of cell types. However, the mechanistic basis for these effects is unclear. In part, this uncertainty has arisen because the cell-surface receptor molecules that interact with sAPPα are not known. Previous studies have reported that sAPPα may interact with a novel lipid-raft type membrane domain in the cell. Furthermore, sAPPα has been reported to bind to the lipid GM1-ganglioside. On the basis of these reports, the work in this thesis explored the hypothesis that an interaction of APP with cell surface lipids could facilitate binding and/or signalling by sAPPα. To determine if sAPPα is able to interact with a sub-group of lipids. The relative ability of sAPPα to bind to 27 physiological lipids was examined using a proteinlipid overlay assay. This assay identified that sAPPα could bind selectively to phosphoinositide lipids (PIPs). Further, a recombinant fragment of APP corresponding to the E1 N-terminal domain (APP-E1) also bound selectively to PIPs, suggesting there is a PIP-binding region within the E1 domain of APP. To investigate whether APP and PIP could interact on the cell surface, it was first necessary to demonstrate that PIPs are present on the cell surface. A live cell immunolabelling method was used to examine the location of cell surface PIPs. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) immunoreactivity was found to be present on the surface of cells in primary murine hippocampal cultures in discrete puncta <1 μm in size. This observation was also confirmed using a recombinant PI(4,5)P2 biosensor protein. To examine whether APP could interact with cell-surface PIP, studies were performed to examine the degree of colocalisation of exogenous APP-E1 and cellsurface PI(4,5)P2. APP-E1 that was added to primary hippocampal cultures bound to the surface of neurons…

Subjects/Keywords: Alzheimer's disease; Phosphoinositides; beta-amyloid precursor protein; Phosphatidylinositol; phosphate; heparin.

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Dawkins, E. (2014). Role of Phosphoinositides in the biology of the amyloid precursor protein. (Thesis). University of Tasmania. Retrieved from https://eprints.utas.edu.au/18274/1/front-Dawkins-thesis.pdf ; https://eprints.utas.edu.au/18274/2/Whole-Dawkins-thesis.pdf

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Dawkins, E. “Role of Phosphoinositides in the biology of the amyloid precursor protein.” 2014. Thesis, University of Tasmania. Accessed April 10, 2021. https://eprints.utas.edu.au/18274/1/front-Dawkins-thesis.pdf ; https://eprints.utas.edu.au/18274/2/Whole-Dawkins-thesis.pdf.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Dawkins, E. “Role of Phosphoinositides in the biology of the amyloid precursor protein.” 2014. Web. 10 Apr 2021.

Vancouver:

Dawkins E. Role of Phosphoinositides in the biology of the amyloid precursor protein. [Internet] [Thesis]. University of Tasmania; 2014. [cited 2021 Apr 10]. Available from: https://eprints.utas.edu.au/18274/1/front-Dawkins-thesis.pdf ; https://eprints.utas.edu.au/18274/2/Whole-Dawkins-thesis.pdf.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Dawkins E. Role of Phosphoinositides in the biology of the amyloid precursor protein. [Thesis]. University of Tasmania; 2014. Available from: https://eprints.utas.edu.au/18274/1/front-Dawkins-thesis.pdf ; https://eprints.utas.edu.au/18274/2/Whole-Dawkins-thesis.pdf

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Texas Southwestern Medical Center

19. Warren, Rebekkah Lynn. Genetic Reduction of Cholesterol Synthesis in the Mouse Brain Does Not Affect Amyloid Formation in an Alzheimer’s Disease Model, but Does Extend Lifespan.

Degree: 2011, University of Texas Southwestern Medical Center

URL: http://hdl.handle.net/2152.5/891

► In vitro alterations in cellular cholesterol content or synthesis affect the cleavage of amyloid precursor protein (APP) to amyloidogenic peptides characteristic of Alzheimer’s disease (AD).… (more)

Subjects/Keywords: Amyloid beta-Protein Precursor; Alzheimer Disease; Lipid Metabolism

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Warren, R. L. (2011). Genetic Reduction of Cholesterol Synthesis in the Mouse Brain Does Not Affect Amyloid Formation in an Alzheimer’s Disease Model, but Does Extend Lifespan. (Thesis). University of Texas Southwestern Medical Center. Retrieved from http://hdl.handle.net/2152.5/891

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Warren, Rebekkah Lynn. “Genetic Reduction of Cholesterol Synthesis in the Mouse Brain Does Not Affect Amyloid Formation in an Alzheimer’s Disease Model, but Does Extend Lifespan.” 2011. Thesis, University of Texas Southwestern Medical Center. Accessed April 10, 2021. http://hdl.handle.net/2152.5/891.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Warren, Rebekkah Lynn. “Genetic Reduction of Cholesterol Synthesis in the Mouse Brain Does Not Affect Amyloid Formation in an Alzheimer’s Disease Model, but Does Extend Lifespan.” 2011. Web. 10 Apr 2021.

Vancouver:

Warren RL. Genetic Reduction of Cholesterol Synthesis in the Mouse Brain Does Not Affect Amyloid Formation in an Alzheimer’s Disease Model, but Does Extend Lifespan. [Internet] [Thesis]. University of Texas Southwestern Medical Center; 2011. [cited 2021 Apr 10]. Available from: http://hdl.handle.net/2152.5/891.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Warren RL. Genetic Reduction of Cholesterol Synthesis in the Mouse Brain Does Not Affect Amyloid Formation in an Alzheimer’s Disease Model, but Does Extend Lifespan. [Thesis]. University of Texas Southwestern Medical Center; 2011. Available from: http://hdl.handle.net/2152.5/891

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Adelaide

20. Plummer, Stephanie Lauren. Investigating amyloid precursor protein derivatives as novel therapeutic agents following traumatic brain injury.

Degree: 2017, University of Adelaide

URL: http://hdl.handle.net/2440/126463

► Despite the significant health and economic burden that traumatic brain injury (TBI) places on society, the development of successful therapeutic agents to reduce its burden… (more)

▼ Despite the significant health and economic burden that traumatic brain injury (TBI) places on society, the development of successful therapeutic agents to reduce its burden has not been successful. The Amyloid Precursor Protein (APP) is an ideal therapeutic candidate, as its acute upregulation following TBI has been shown to serve a number of neuroprotective roles following TBI. Recently, the APP derivative APP96 110, a 15 amino acid length peptide derivative, has continued to display these neuroprotective and neurotrophic functions. While the mechanisms for this remain unclear, it is hypothesized that these neuroprotective properties are linked to its ability to bind to heparin, and that these regions are responsible for the protection against neuronal injury and the improvement in neurological outcome following TBI. In order to further develop APP96 110 as a novel and clinically relevant therapeutic agent following TBI, it was essential to determine the optimal dose, route of and timepoint for administration, as well as examining ways in which the neuroprotective response of this peptide could be further enhanced. In order to investigate these, a dose response study was carried out in male Sprague Dawley rats that was the first to assess the efficacy of intravenous (IV) APP96 110 acutely at 30 minutes post TBI, followed by the more clinically relevant 5 hour timepoint. IV administration of APP96 110 was shown to be neuroprotective for up to 5 hours post TBI, with animals demonstrating improvements in motor outcome and reductions in axonal injury (AI) and neuroinflammation when treated with the highest dose. Studies also assessed the ability to generate APP analogues with alterations to the amino acid sequence, to enhance the heparin binding affinity of the peptide, and examine whether this translated to increased neuroprotection following TBI. Mutation of the APP96 110 peptide to enhance its heparin binding affinity resulted in a peptide with a stronger affinity for heparin (3+APP96 110), and in vivo, resulted in smaller doses conferring equal neuroprotective action to higher doses of wildtype (WT) APP96 110 post TBI. In addition, the long term efficacy of these APP96 110 derivatives was examined, with emphasis placed on assessing long term functional outcome, and beginning to elucidate the long term neuroinflammatory and neurodegenerative changes. Assessment of the long term efficacy demonstrated that, whilst WT and 3+APP96 110 produced similar protection for neuroinflammation, axonal structure, myelination, synaptogenesis and neurodegeneration, treatment with 3+APP96 110 significantly outperformed WT APP96 110 in its ability to improve functional outcome. Together, results demonstrate that the neuroprotective benefits of APP96 110 may relate to its heparin binding ability, with this binding playing a crucial role in the mechanisms though which APP96 110 can exert their neuroprotective actions post TBI. Overall, APP96 110 shows promise as a novel and clinically relevant treatment option, that could overcome many… Advisors/Committee Members: Van Den Heuvel, Corinna (advisor), Thornton, Emma (advisor), Corrigan, Frances (advisor), Cappai, Roberto (advisor), Adelaide Medical School (school).

Subjects/Keywords: Amyloid precursor protein; traumatic brain injury; inflamamtion; axonal injury

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Plummer, S. L. (2017). Investigating amyloid precursor protein derivatives as novel therapeutic agents following traumatic brain injury. (Thesis). University of Adelaide. Retrieved from http://hdl.handle.net/2440/126463

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Plummer, Stephanie Lauren. “Investigating amyloid precursor protein derivatives as novel therapeutic agents following traumatic brain injury.” 2017. Thesis, University of Adelaide. Accessed April 10, 2021. http://hdl.handle.net/2440/126463.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Plummer, Stephanie Lauren. “Investigating amyloid precursor protein derivatives as novel therapeutic agents following traumatic brain injury.” 2017. Web. 10 Apr 2021.

Vancouver:

Plummer SL. Investigating amyloid precursor protein derivatives as novel therapeutic agents following traumatic brain injury. [Internet] [Thesis]. University of Adelaide; 2017. [cited 2021 Apr 10]. Available from: http://hdl.handle.net/2440/126463.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Plummer SL. Investigating amyloid precursor protein derivatives as novel therapeutic agents following traumatic brain injury. [Thesis]. University of Adelaide; 2017. Available from: http://hdl.handle.net/2440/126463

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Otago

21. Morris, Gary Paul. Secreted amyloid precursor protein-α mediates neuroprotection and gene expression .

Degree: 2011, University of Otago

URL: http://hdl.handle.net/10523/2026

► Alzheimer’s disease (AD) is rapidly becoming one of the most significant challenges facing modern medicine. Currently there is no cure for this neurodegenerative disease. Memory… (more)

▼ Alzheimer’s disease (AD) is rapidly becoming one of the most significant challenges facing modern medicine. Currently there is no cure for this neurodegenerative disease. Memory defects arise from gross atrophy of specific brain regions and intensive research efforts have focused on the central role of a toxic build up of the amyloid-β (Aβ) protein. The amyloid-β precursor protein (APP) may play a key role in the pathogenesis of AD as it is proteolytically processed to produce Aβ. APP can also be processed via a mutually exclusive non-amyloidogenic pathway, to produce secreted amyloid precursor protein-α (sAPPα). sAPPα is neurotrophic and neuroprotective, and can restore memory mechanisms, contrasting the negative effects of Aβ. The balance between the concentration of Aβ and sAPPα may be important, with an increase in Aβ and a decrease in sAPPα potentially contributing to the pathology of AD. sAPPα stimulates the activity of a number of signalling pathways, however downstream genetic targets of these cascades have not yet been fully established. Recently, small peptide motifs within sAPPα have been shown to be capable of mimicking sAPPα’s functions, and may provide novel therapeutic agents for the treatment of AD. It is unknown what role the smallest reported bioactive motif, RER, plays within the full-length protein. Furthermore, it is unclear if RER is capable of mimicking the neuroprotective and gene expression inducing functions of sAPPα, critical for its success as a therapeutic peptide. This project has applied biochemical and molecular biological techniques to characterize the neuroprotective effects of sAPPα, and to determine the ability of sAPPα to stimulate gene expression. The role of the RER motif in full-length sAPPα, and as a dissociated tripeptide, has been evaluated. A variant sAPPα protein, sAPPαAER (designed and produced in the research group) was purified, and assayed along with a chemically synthesized RER peptide for both neuroprotection and the ability to induce gene expression. sAPPα’s effects on the transcriptome of organotypic rat hippocampal slices was assessed using microarray analysis. These results have shown that sAPPα is indeed neuroprotective and capable of rapidly inducing the expression of several genes as early as 15-30min. The sAPPαAER variant was as effective as the native sAPPα in producing these effects, indicating other active domains may be present within the sAPPα protein. Nevertheless, the isolated RER tripeptide is capable of mimicking the neuroprotective and gene expression inducing effects of full-length sAPPα. Through microarray analysis of organotypic hippocampal slices, this study has uncovered several new putative targets for sAPPα signalling. sAPPα rapidly activated the expression of immediate early genes, several miRNA precursor genes, and genes with neurotrophic functions. Over a longer period of treatment sAPPα modulated a different set of genes related to immune responses, cellular proliferation, inflammation, transcription and survival. Advisors/Committee Members: Tate, Warren P (advisor).

Subjects/Keywords: secreted amyloid precursor protein; Alzheimer's; gene expression; RER; sAPPα

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Morris, G. P. (2011). Secreted amyloid precursor protein-α mediates neuroprotection and gene expression . (Masters Thesis). University of Otago. Retrieved from http://hdl.handle.net/10523/2026

Chicago Manual of Style (16^th Edition):

Morris, Gary Paul. “Secreted amyloid precursor protein-α mediates neuroprotection and gene expression .” 2011. Masters Thesis, University of Otago. Accessed April 10, 2021. http://hdl.handle.net/10523/2026.

MLA Handbook (7^th Edition):

Morris, Gary Paul. “Secreted amyloid precursor protein-α mediates neuroprotection and gene expression .” 2011. Web. 10 Apr 2021.

Vancouver:

Morris GP. Secreted amyloid precursor protein-α mediates neuroprotection and gene expression . [Internet] [Masters thesis]. University of Otago; 2011. [cited 2021 Apr 10]. Available from: http://hdl.handle.net/10523/2026.

Council of Science Editors:

Morris GP. Secreted amyloid precursor protein-α mediates neuroprotection and gene expression . [Masters Thesis]. University of Otago; 2011. Available from: http://hdl.handle.net/10523/2026

University of Illinois – Chicago

22. Demars, Michael P. Soluble Amyloid Precursor Protein Regulates Neurogenesis: Implications for Brain Repair.

Degree: 2012, University of Illinois – Chicago

URL: http://hdl.handle.net/10027/9149

► Amyloid precursor protein (APP) has been studied extensively in the pathophysiology of Alzheimer’s disease due to the fact that mutations in APP are causative of… (more)

▼ Amyloid precursor protein (APP) has been studied extensively in the pathophysiology of Alzheimer’s disease due to the fact that mutations in APP are causative of familial forms of the disease. However, the physiological significance of the protein has yet to be fully elucidated. APP undergoes sequential metabolism through two distinct pathways involving three enzymatic cleavage events via enzymes termed α-, β, and γ-secretase. These cleavage events produce a number of intra- and extra-cellular metabolites that add complexity to the potential physiological function of APP. α-secretase cleavage produces a soluble extracellular metabolite, soluble amyloid precursor protein alpha (sAPPα), that has been previously shown to have trophic characteristics and contain a cysteine-rich growth factor like domain. In the adult brain, neural progenitor cells (NPC) represent a proliferating population of cells that have the ability to form new neurons in discrete regions. These NPC have been shown to have binding sites for sAPP. In Alzheimer’s disease and normal aging, there is a dramatic decline in the adult neurogenesis. We hypothesized that sAPPα is a growth factor for NPC of the adult brain and alterations in the metabolism of APP/sAPPα during normal aging or in Alzheimer’s disease could contribute to stem cell senescence. In this work we show that sAPPα potently stimulates the proliferation of NPC following α-secretase inhibition independently of epidermal growth factor or basic fibroblast growth factor. Further, sAPPα induces phosphorylation of extracellular signal-regulated kinase (Erk) and transcription of genes associated with cell cycle, neurogenesis and energy metabolism. The soluble metabolite derived from the alternative, pathological, cleavage pathway of APP, sAPPβ, shows only slight proliferative qualities in NPC suggesting that alterations in the normal cleavage pattern of APP could underlie neurogenic impairments in Alzheimer’s disease. Finally, we show that sAPP levels decline with age in a manner that correlates with the timing of neurogenic decline and that a single intracerebroventricular injection of sAPPα is sufficient to ameliorate aging-linked deficits in neurogenesis. Taken together, these results suggest that sAPPα is a proliferation factor for NPC of the adult brain whose decline in aging or Alzheimer’s disease could contribute to neurogenic deficits. Advisors/Committee Members: Unnerstall, James (advisor), Lazarov, Orly (committee member), Brady, Scott (committee member), Larson, John (committee member), Marr, Robert (committee member).

Subjects/Keywords: amyloid precursor protein; neurogenesis; neural progenitor cell; proliferation; Alzheimer's disease

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Demars, M. P. (2012). Soluble Amyloid Precursor Protein Regulates Neurogenesis: Implications for Brain Repair. (Thesis). University of Illinois – Chicago. Retrieved from http://hdl.handle.net/10027/9149

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Demars, Michael P. “Soluble Amyloid Precursor Protein Regulates Neurogenesis: Implications for Brain Repair.” 2012. Thesis, University of Illinois – Chicago. Accessed April 10, 2021. http://hdl.handle.net/10027/9149.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Demars, Michael P. “Soluble Amyloid Precursor Protein Regulates Neurogenesis: Implications for Brain Repair.” 2012. Web. 10 Apr 2021.

Vancouver:

Demars MP. Soluble Amyloid Precursor Protein Regulates Neurogenesis: Implications for Brain Repair. [Internet] [Thesis]. University of Illinois – Chicago; 2012. [cited 2021 Apr 10]. Available from: http://hdl.handle.net/10027/9149.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Demars MP. Soluble Amyloid Precursor Protein Regulates Neurogenesis: Implications for Brain Repair. [Thesis]. University of Illinois – Chicago; 2012. Available from: http://hdl.handle.net/10027/9149

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Bath

23. Hammond, Victoria. α7 nicotinic acetylcholine receptors at the glutamatergic synapse.

Degree: PhD, 2014, University of Bath

URL: https://researchportal.bath.ac.uk/en/studentthesis/7-nicotinic-acetylcholine-receptors-at-the-glutamatergic-synapse(8e4bcf14-fe9b-446a-a56e-fda3ba2c2eb4).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.633163

► Nicotinic acetylcholine receptor (nAChR) activation is neuroprotective and nicotine is a cognitive enhancer. Loss of nAChRs, deposition of tau neurofibrillary tangles, cleavage of amyloid precursor… (more)

▼ Nicotinic acetylcholine receptor (nAChR) activation is neuroprotective and nicotine is a cognitive enhancer. Loss of nAChRs, deposition of tau neurofibrillary tangles, cleavage of amyloid precursor protein (APP) and inflammation are well documented in the pathogenesis of Alzheimer’s disease (AD). Sequential cleavage of APP by β- and γ-secretase enzymes generates soluble Aβ peptides, with oligomeric forms of Aβ implicated in both the control of synaptic excitability and dysregulation of synaptic transmission and induction of neuronal death in AD. Aβ production is inhibited by calcium-dependent recruitment of α-secretase, as exemplified by activation of N-methyl-D-aspartate receptors (NMDAR). All neurodegenerative diseases are associated with inflammation, arising from altered homeostasis of the innate immune system, resulting in heightened activation of immune cells and induction of a pro-inflammatory environment. Stimulation of the α7 subtype of nAChR is anti-inflammatory and also enhances cognition and promotes neuronal survival. This work addressed the hypotheses that stimulation of highly calcium-permeable α7nAChR inhibits Aβ production by promoting α-secretase-mediated processing of APP and also modulates inflammatory cellular behaviour of microglia. Thus, this study assessed the role of α7nAChR at glutamatergic synapses, through probing effects on APP processing and phagocytosis in primary cortical neurons and microglia, respectively. Primary cortical neurons expressed functional α7nAChR and glutamate receptors, and through a number of experimental approaches, including immunoblotting and a cleavage reporter assay, results indicated α7nAChR activation with the α7nAChR-selective agonist PNU-282987 and positive allosteric modulator PNU-120596 had no effect on APP and Tau, in contrast to NMDAR activation that significantly modulated these proteins. Data suggest low expression of α7nAChR, coupled with distinct localisation of presynaptic α7nAChR and postsynaptic APP could explain the lack of effect. In addition, primary microglia were highly responsive to lipopolysaccharide and possessed functional α7nAChR that coupled to ERK phosphorylation. Microglial α7nAChR activation promoted neuroprotective phagocytic behaviour, in agreement with the ‘cholinergic anti-inflammatory pathway’. This study supports the hypothesis that α7nAChR are modulators of anti-inflammatory behaviour, thus α7nAChR-selective ligands are viable candidates for the treatment of AD and promoting cognitive enhancement.

Subjects/Keywords: 612.8; nicotinic acetylcholine receptors; amyloid precursor protein; Neuron; Microglia

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Hammond, V. (2014). α7 nicotinic acetylcholine receptors at the glutamatergic synapse. (Doctoral Dissertation). University of Bath. Retrieved from https://researchportal.bath.ac.uk/en/studentthesis/7-nicotinic-acetylcholine-receptors-at-the-glutamatergic-synapse(8e4bcf14-fe9b-446a-a56e-fda3ba2c2eb4).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.633163

Chicago Manual of Style (16^th Edition):

Hammond, Victoria. “α7 nicotinic acetylcholine receptors at the glutamatergic synapse.” 2014. Doctoral Dissertation, University of Bath. Accessed April 10, 2021. https://researchportal.bath.ac.uk/en/studentthesis/7-nicotinic-acetylcholine-receptors-at-the-glutamatergic-synapse(8e4bcf14-fe9b-446a-a56e-fda3ba2c2eb4).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.633163.

MLA Handbook (7^th Edition):

Hammond, Victoria. “α7 nicotinic acetylcholine receptors at the glutamatergic synapse.” 2014. Web. 10 Apr 2021.

Vancouver:

Hammond V. α7 nicotinic acetylcholine receptors at the glutamatergic synapse. [Internet] [Doctoral dissertation]. University of Bath; 2014. [cited 2021 Apr 10]. Available from: https://researchportal.bath.ac.uk/en/studentthesis/7-nicotinic-acetylcholine-receptors-at-the-glutamatergic-synapse(8e4bcf14-fe9b-446a-a56e-fda3ba2c2eb4).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.633163.

Council of Science Editors:

Hammond V. α7 nicotinic acetylcholine receptors at the glutamatergic synapse. [Doctoral Dissertation]. University of Bath; 2014. Available from: https://researchportal.bath.ac.uk/en/studentthesis/7-nicotinic-acetylcholine-receptors-at-the-glutamatergic-synapse(8e4bcf14-fe9b-446a-a56e-fda3ba2c2eb4).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.633163

Université Catholique de Louvain

24. Perrin, Florian. Molecular determinants regulating dimerization, processing and signaling of the amyloid precursor protein.

Degree: 2019, Université Catholique de Louvain

URL: http://hdl.handle.net/2078.1/219632

►

Alzheimer’s disease (AD) is characterized by cognitive impairments such as apraxia, aphasia and memory decline. The two majors hallmarks of AD are neurofibrillary tangles and… (more)

Subjects/Keywords: Alzheimer's disease; Amyloid Precursor Protein; Dimerization; Oligomerization; Orientation; Processing

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Perrin, F. (2019). Molecular determinants regulating dimerization, processing and signaling of the amyloid precursor protein. (Thesis). Université Catholique de Louvain. Retrieved from http://hdl.handle.net/2078.1/219632

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Perrin, Florian. “Molecular determinants regulating dimerization, processing and signaling of the amyloid precursor protein.” 2019. Thesis, Université Catholique de Louvain. Accessed April 10, 2021. http://hdl.handle.net/2078.1/219632.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Perrin, Florian. “Molecular determinants regulating dimerization, processing and signaling of the amyloid precursor protein.” 2019. Web. 10 Apr 2021.

Vancouver:

Perrin F. Molecular determinants regulating dimerization, processing and signaling of the amyloid precursor protein. [Internet] [Thesis]. Université Catholique de Louvain; 2019. [cited 2021 Apr 10]. Available from: http://hdl.handle.net/2078.1/219632.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Perrin F. Molecular determinants regulating dimerization, processing and signaling of the amyloid precursor protein. [Thesis]. Université Catholique de Louvain; 2019. Available from: http://hdl.handle.net/2078.1/219632

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Melbourne

25. BARAKAT, ADEL. Investigation of neuregulin1 processing by BACE1 and gamma-secretase in schizophrenia.

Degree: 2014, University of Melbourne

URL: http://hdl.handle.net/11343/39642

► Schizophrenia is a multifactorial complex psychiatric illness, which implicates many genes, among which is neuregulin1 (Nrg1). BACE1 and γ-secretase are known to be involved in… (more)

▼ Schizophrenia is a multifactorial complex psychiatric illness, which implicates many genes, among which is neuregulin1 (Nrg1). BACE1 and γ-secretase are known to be involved in the proteolytic processing of the Alzheimer’s disease-associated Amyloid Precursor Protein (APP), but they are also required for processing Nrg1 type III. Thus, perturbation of the proteolytic activity of these enzymes would disrupt Nrg1 signalling, and could be associated with schizophrenia (SCZ). Indeed, knockout of BACE1 or γ-secretase subunit APH-1b in mice causes SCZ-like phenotypes due to the miscleavage of Nrg1. Also, clinical profile analysis and genetic studies support presenilin2 (PS2), another γ-secretase subunit, as a susceptibility gene for SCZ. Therefore, we proposed to investigate further the expression of BACE1 and γ-secretase subunits, APH-1b and PS2, in SCZ subjects. Human brain samples from Brodmann area 6 (39 SCZ and 20 HC) were obtained from the Victorian Brain Bank. Our previous studies with these samples showed a 50% decrease in Nrg1-CTF in the SCZ group compared to HC. Western blotting analysis of BACE1 and APH-1b indicated no significant difference in the expression of these proteins between SCZ and HC. Notably, a correlation was found between BACE1 and APH-1b, in the HC group, but not in the SCZ group. In this thesis, RNA was analysed by qRT-PCR to identify and quantify the expression of four BACE1 splice variants (SV), APH-1b and PS2 mRNA. Data were analysed and expressed relative to two endogenous controls (UBC and RPLP0). BACE1 enzymatic activity of human brain samples was measured using a synthetic APP peptide cleavage assay. The four BACE1 SV were cloned in the pcDNA3.1+ mammalian expression vector and transfected in SH-SY5Y cells. The cells were analysed for BACE1 enzymatic activity using an in vitro assay, and by analysis of APP and Nrg1 cleavage products and measurement of Aβ secretion by ELISA. The colocalization of Nrg1, BACE1 SV and APP in SY5Y transfected cells was investigated by immunofluorescence (IF) microscopy. Subcellular fractionation was used to explore the trafficking of Nrg1, BACE1 SV and APP in transfected cell organelles. Results of qRT-PCR showed a statistically significant two-fold increase in the expression of BACE1 432 SV in the SCZ group compared to HC. No significant difference was found in the expression levels of APH-1b and PS2 mRNA, but significant correlations were discovered for APH-1b and PS2 in SCZ and HC groups. Particularly, there was a significant positive correlation between APH-1b and PS2 in the HC group that was not preserved in SCZ. Enzymatic assay and ELISA of cells transfected with BACE1 SV indicated high BACE1 enzymatic activity for BACE1 501 SV, and little or no activity for the other SV, including 432. It showed partial colocalisation between BACE1 SV, Nrg1 and APP. Also subcellular fractionation indicated disturbed BACE1 trafficking due to overexpression of BACE1 SV. We report for the first time a significant increase of BACE1 432 SV in SCZ premotor…

Subjects/Keywords: neuroscience; schizophrenia; secretase; BACE1; gamma secretase; neuregulin1; amyloid precursor protein

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

BARAKAT, A. (2014). Investigation of neuregulin1 processing by BACE1 and gamma-secretase in schizophrenia. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/39642

Chicago Manual of Style (16^th Edition):

BARAKAT, ADEL. “Investigation of neuregulin1 processing by BACE1 and gamma-secretase in schizophrenia.” 2014. Doctoral Dissertation, University of Melbourne. Accessed April 10, 2021. http://hdl.handle.net/11343/39642.

MLA Handbook (7^th Edition):

BARAKAT, ADEL. “Investigation of neuregulin1 processing by BACE1 and gamma-secretase in schizophrenia.” 2014. Web. 10 Apr 2021.

Vancouver:

BARAKAT A. Investigation of neuregulin1 processing by BACE1 and gamma-secretase in schizophrenia. [Internet] [Doctoral dissertation]. University of Melbourne; 2014. [cited 2021 Apr 10]. Available from: http://hdl.handle.net/11343/39642.

Council of Science Editors:

BARAKAT A. Investigation of neuregulin1 processing by BACE1 and gamma-secretase in schizophrenia. [Doctoral Dissertation]. University of Melbourne; 2014. Available from: http://hdl.handle.net/11343/39642

University of Melbourne

26. GAO, CHEN. Structural and biophysical characterisation of Alzheimer’s disease amyloid precursor protein.

Degree: 2015, University of Melbourne

URL: http://hdl.handle.net/11343/55553

► Alzheimer’s disease (AD) is an irreversible, neurodegenerative disorder most commonly affecting the aged population. Despite the growing incidence world wide, the disease remains untreatable due… (more)

▼ Alzheimer’s disease (AD) is an irreversible, neurodegenerative disorder most commonly affecting the aged population. Despite the growing incidence world wide, the disease remains untreatable due to a lack of understanding of the disease mechanism. Central to AD etiology is the amyloid cascade hypothesis, which states that the accumulation of a toxic peptide amyloid-beta (Abeta) sets off a cascade of cytotoxic events leading to the death of neurons. Abeta is derived from the amyloid precursor protein (APP). APP is a type-I ransmembrane protein with a large ectodomain (sAPP), a single transmembrane domain and a cytoplasmic tail. Its dimerisation has been closely linked to Aβ overproduction, and is also implicated in signalling as APP is proposed to be a membrane receptor. There are four putative dimerisation sites in APP, three of which are located in the sAPP region. However, the mechanisms of APP dimerisation remains unclear. Understanding APP dimerisation mechanisms at the molecular level will not only provide insights into how APP signals but also have therapeutic implications. Several factors are found to regulate APP proteolysis in vivo. To test their impact on sAPP dimerisation, different fragments of sAPP containing distinct dimerisation domains were expressed as recombinant proteins and subjected to extensive dimerisation studies in vitro. pH, zinc and long-chain heparin were found to be the three major modulators of sAPP stability and dimerisation. Interestingly, sAPP fragments containing different dimerisation domains respond differently to the three modulators: the C-terminal fragment of sAPP containing three of the four dimerisation sites can be stabilised by low pH and zinc, but only forms dimers in the presence of long-chain heparin. In contrast, the N-terminal fragment of sAPP containing two of the dimerisation domains was found to dimerise at higher pH and in the presence of zinc. Such differences in the dimerisation behaviour between different regions of sAPP suggest the dimerisation mechanism of the full-length APP is much more complex than previously thought. Results from the dimerisation studies led to the successful crystallisation of the sAPP C-terminal region in the presence of zinc and long-chain heparin in unique dimeric forms. The structure derived from the crystals reveals the dimer is stabilised by six zinc ions. The observation of a heparin disaccharide at the two-fold symmetry axis also led to the construction of two long-chain heparin mediated APP dimer models, one of which is consistent with the requirement of long-chain heparin to stabilise the dimer. A dodecapeptide from the juxtamembrane region of APP was observed to interact with the metal-binding E2 domain of APP via two zinc ions; this interaction is accompanied by the formation of a partial helix in the otherwise unstructured peptide. Interestingly, a familial AD mutation P545L (P620L in the longest APP isoform) is located near one of the zinc binding sites in the peptide, suggesting the zinc-mediated peptide/E2…

Subjects/Keywords: amyloid precursor protein; Alzheimer's; dimerisation; X-ray crystallography; structural biology

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

GAO, C. (2015). Structural and biophysical characterisation of Alzheimer’s disease amyloid precursor protein. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/55553

Chicago Manual of Style (16^th Edition):

GAO, CHEN. “Structural and biophysical characterisation of Alzheimer’s disease amyloid precursor protein.” 2015. Doctoral Dissertation, University of Melbourne. Accessed April 10, 2021. http://hdl.handle.net/11343/55553.

MLA Handbook (7^th Edition):

GAO, CHEN. “Structural and biophysical characterisation of Alzheimer’s disease amyloid precursor protein.” 2015. Web. 10 Apr 2021.

Vancouver:

GAO C. Structural and biophysical characterisation of Alzheimer’s disease amyloid precursor protein. [Internet] [Doctoral dissertation]. University of Melbourne; 2015. [cited 2021 Apr 10]. Available from: http://hdl.handle.net/11343/55553.

Council of Science Editors:

GAO C. Structural and biophysical characterisation of Alzheimer’s disease amyloid precursor protein. [Doctoral Dissertation]. University of Melbourne; 2015. Available from: http://hdl.handle.net/11343/55553

University of Melbourne

27. TOH, WEI. The intracellular trafficking pathways of β-secretase and the amyloid precursor protein in Alzheimer’s disease.

Degree: 2015, University of Melbourne

URL: http://hdl.handle.net/11343/55767

► Alzheimer’s disease (AD) is characterized by the accumulation of amyloid plaques in the brain consisting of an aggregated form of β-amyloid peptide (Aβ) derived from… (more)

▼ Alzheimer’s disease (AD) is characterized by the accumulation of amyloid plaques in the brain consisting of an aggregated form of β-amyloid peptide (Aβ) derived from sequential amyloidogenic processing of the Amyloid Precursor Protein (APP) by membrane-bound proteases BACE1 and γ-secretase. The trafficking of these components in the amyloidogenic pathway is thought to influence the levels of Aβ production. In fact, GWAS (Genome wide sequencing studies) has identified several AD susceptibility genes that are associated with the regulation of membrane trafficking (Harold et al., 2009, Lambert et al., 2009, Lee et al., 2011), suggesting that AD could be a result of defective membrane trafficking. The main aims of my thesis were to 1) define the intracellular trafficking itineraries of BACE1 and APP, 2) identify the sorting signals of BACE1 and the molecular machinery responsible for BACE1 endosomal transport, 3) identify the anterograde transport pathways of BACE1 and APP and lastly, 4) investigate the intracellular localization of endogenous BACE1 and APP in mouse primary cortical neurons and the influence of neuronal stimulation on their localization. Knowledge of the intracellular trafficking pathways of BACE1 and APP remain only poorly defined. Previous studies have suggested that BACE1 recycles via the trans-Golgi network (TGN) while APP is trafficked to either the TGN or the late endosome. In Chapter 3, I showed BACE1 is rapidly internalized from the plasma membrane and subsequently traffics to the early endosomes and Rab11-positive, juxtanuclear recycling endosomes in a number of cell lines, including neuronal cells whereas very little internalised BACE1 is transported to the TGN. In contrast, the majority of the internalized APP traffics to the late endosomes/ lysosomes. Events that may alter the kinetics of endosomal sorting of BACE1 or APP would alter the residency time of either protein in endosomes which may impact on Aβ production. In Chapter 4, I assessed the mechanisms that regulate endosomal sorting of BACE1. A phosphorylated DISLL motif has been identified in the cytoplasmic tail of BACE1 in vivo which may be involved in endosomal sorting (Walter et al., 2001). To explore a role for this DISLL motif in early endosome-to-recycling endosome trafficking, the impact of Ser498 phosphorylation on this trafficking step was examined. Using antibody internalization assays, the phosphomimetic S498D mutant of BACE1 was found to traffic to the recycling endosomes at a faster rate compared to wild-type BACE1 while the non-phosphorylatable S498A mutant traffics to the recycling endosomes at a slower rate. Increased residency time of BACE1 S498A in the early endosome resulted increased Aβ production while expression of BACE1 S498D reduced Aβ production. These results suggest that phosphorylation of the BACE1 sorting motif can alter residency time of BACE1 in the early endosomes which in turns affects Aβ production. Expression of BACE1 phospho-mutants in mouse primary cortical neurons showed that BACE1 S498A…

Subjects/Keywords: Amyloid precursor protein; Beta-secretase, BACE1; Membrane trafficking; Alzheimer's disease

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

TOH, W. (2015). The intracellular trafficking pathways of β-secretase and the amyloid precursor protein in Alzheimer’s disease. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/55767

Chicago Manual of Style (16^th Edition):

TOH, WEI. “The intracellular trafficking pathways of β-secretase and the amyloid precursor protein in Alzheimer’s disease.” 2015. Doctoral Dissertation, University of Melbourne. Accessed April 10, 2021. http://hdl.handle.net/11343/55767.

MLA Handbook (7^th Edition):

TOH, WEI. “The intracellular trafficking pathways of β-secretase and the amyloid precursor protein in Alzheimer’s disease.” 2015. Web. 10 Apr 2021.

Vancouver:

TOH W. The intracellular trafficking pathways of β-secretase and the amyloid precursor protein in Alzheimer’s disease. [Internet] [Doctoral dissertation]. University of Melbourne; 2015. [cited 2021 Apr 10]. Available from: http://hdl.handle.net/11343/55767.

Council of Science Editors:

TOH W. The intracellular trafficking pathways of β-secretase and the amyloid precursor protein in Alzheimer’s disease. [Doctoral Dissertation]. University of Melbourne; 2015. Available from: http://hdl.handle.net/11343/55767

University of Georgia

28. Gupta, Nisha. Association of Hirano bodies and C31 fragment of the amyloid precursor protein.

Degree: 2014, University of Georgia

URL: http://hdl.handle.net/10724/25811

► Hirano bodies are cellular inclusions found in patients suffering from neurodegenerative diseases. However, the physiological function of Hirano bodies is not understood. A previous study… (more)

Subjects/Keywords: Hirano bodies; amyloid precursor protein; C31; Alzheimer’s disease

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Gupta, N. (2014). Association of Hirano bodies and C31 fragment of the amyloid precursor protein. (Thesis). University of Georgia. Retrieved from http://hdl.handle.net/10724/25811

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Gupta, Nisha. “Association of Hirano bodies and C31 fragment of the amyloid precursor protein.” 2014. Thesis, University of Georgia. Accessed April 10, 2021. http://hdl.handle.net/10724/25811.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Gupta, Nisha. “Association of Hirano bodies and C31 fragment of the amyloid precursor protein.” 2014. Web. 10 Apr 2021.

Vancouver:

Gupta N. Association of Hirano bodies and C31 fragment of the amyloid precursor protein. [Internet] [Thesis]. University of Georgia; 2014. [cited 2021 Apr 10]. Available from: http://hdl.handle.net/10724/25811.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Gupta N. Association of Hirano bodies and C31 fragment of the amyloid precursor protein. [Thesis]. University of Georgia; 2014. Available from: http://hdl.handle.net/10724/25811

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Bridgeport

29. Sanders, Kimberly M. Amyloid Precursor Protein Processing in Autism and Alzheimer’s Disease and the Potential Therapeutic Use of Trehalose .

Degree: 2013, University of Bridgeport

URL: https://scholarworks.bridgeport.edu/xmlui/handle/123456789/1396

► Multiple neurodegenerative diseases, including Alzheimer’s disease and autism, are associated with the presence of amyloid material in the brain which has been shown to lead… (more)

Subjects/Keywords: Naturopathy; Autism; Alzheimer’s disease; Amyloid precursor protein; Amyloid beta; Amyloid plaques; Trehalose; Autophagy; Mechanistic target of rapamycin (mTOR)

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Sanders, K. M. (2013). Amyloid Precursor Protein Processing in Autism and Alzheimer’s Disease and the Potential Therapeutic Use of Trehalose . (Thesis). University of Bridgeport. Retrieved from https://scholarworks.bridgeport.edu/xmlui/handle/123456789/1396

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Sanders, Kimberly M. “Amyloid Precursor Protein Processing in Autism and Alzheimer’s Disease and the Potential Therapeutic Use of Trehalose .” 2013. Thesis, University of Bridgeport. Accessed April 10, 2021. https://scholarworks.bridgeport.edu/xmlui/handle/123456789/1396.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Sanders, Kimberly M. “Amyloid Precursor Protein Processing in Autism and Alzheimer’s Disease and the Potential Therapeutic Use of Trehalose .” 2013. Web. 10 Apr 2021.

Vancouver:

Sanders KM. Amyloid Precursor Protein Processing in Autism and Alzheimer’s Disease and the Potential Therapeutic Use of Trehalose . [Internet] [Thesis]. University of Bridgeport; 2013. [cited 2021 Apr 10]. Available from: https://scholarworks.bridgeport.edu/xmlui/handle/123456789/1396.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Sanders KM. Amyloid Precursor Protein Processing in Autism and Alzheimer’s Disease and the Potential Therapeutic Use of Trehalose . [Thesis]. University of Bridgeport; 2013. Available from: https://scholarworks.bridgeport.edu/xmlui/handle/123456789/1396

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Johannes Gutenberg Universität Mainz

30. Isbert, Simone. Cellular localization and mechanism of amyloid precursor protein (APP) homodimer formation in an oxidizing environment.

Degree: 2012, Johannes Gutenberg Universität Mainz

URL: http://ubm.opus.hbz-nrw.de/volltexte/2012/3047/

► The amyloid precursor protein (APP) is a type I transmembrane glycoprotein, which resembles a cell surface receptor, comprising a large ectodomain, a single spanning transmembrane… (more)

▼ The amyloid precursor protein (APP) is a type I transmembrane glycoprotein, which resembles a cell surface receptor, comprising a large ectodomain, a single spanning transmembrane part and a short C-terminal, cytoplasmic domain. It belongs to a conserved gene family, with over 17 members, including also the two mammalian APP homologues proteins APLP1 and APLP2 („amyloid precursor like proteins“). APP is encoded by 19 exons, of which exons 7, 8, and 15 can be alternatively spliced to produce three major protein isoforms APP770, APP751 and APP695, reflecting the number of amino acids. The neuronal APP695 is the only isoform that lacks a Kunitz Protease Inhibitor (KPI) domain in its extracellular portion whereas the two larger, peripheral APP isoforms, contain the 57-amino-acid KPI insert. rnRecently, research effort has suggested that APP metabolism and function is thought to be influenced by homodimerization and that the oligomerization state of APP could also play a role in the pathology of Alzheimer's disease (AD), by regulating its processing and amyloid beta production. Several independent studies have shown that APP can form homodimers within the cell, driven by motifs present in the extracellular domain, as well as in the juxtamembrane (JM) and transmembrane (TM) regions of the molecule, whereby the exact molecular mechanism and the origin of dimer formation remains elusive. Therefore, we focused in our study on the actual subcellular origin of APP homodimerization within the cell, an underlying mechanism, and a possible impact on dimerization properties of its homologue APLP1. Furthermore, we analyzed homodimerization of various APP isoforms, in particular APP695, APP751 and APP770, which differ in the presence of a Kunitz-type protease inhibitor domain (KPI) in the extracellular region. In order to assess the cellular origin of dimerization under different cellular conditions, we established a mammalian cell culture model-system in CHO-K1 (chinese hamster ovary) cells, stably overexpressing human APP, harboring dilysine based organelle sorting motifs at the very C-terminus [KKAA-Endoplasmic Reticulum (ER); KKFF-Golgi]. In this study we show that APP exists as disulfide-bound, SDS-stable dimers, when it was retained in the ER, unlike when it progressed further to the cis-Golgi, due to the KKFF ER exit determinant. These stable APP complexes were isolated from cells, and analyzed by SDS–polyacrylamide gel electrophoresis under non-reducing conditions, whereas strong denaturing and reducing conditions completely converted those dimers to monomers. Our findings suggested that APP homodimer formation starts early in the secretory pathway and that the unique oxidizing environment of the ER likely promotes intermolecular disulfide bond formation between APP molecules. We particularly visualized APP dimerization employing a variety of biochemical experiments and investigated the origin of its generation by using a Bimolecular Fluorescence Complementation (BiFC) approach with split GFP-APP chimeras. Moreover, using…

Subjects/Keywords: Amyloid Vorläufer Protein (APP); Dimerisierung; Endoplasmatisches Retikulum; Disulfidbrücken; Amyloid Precursor Protein (APP); Dimerization; Endoplasmic Reticulum; Disulfidebonds; Medical sciences Medicine

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Isbert, S. (2012). Cellular localization and mechanism of amyloid precursor protein (APP) homodimer formation in an oxidizing environment. (Doctoral Dissertation). Johannes Gutenberg Universität Mainz. Retrieved from http://ubm.opus.hbz-nrw.de/volltexte/2012/3047/

Chicago Manual of Style (16^th Edition):

Isbert, Simone. “Cellular localization and mechanism of amyloid precursor protein (APP) homodimer formation in an oxidizing environment.” 2012. Doctoral Dissertation, Johannes Gutenberg Universität Mainz. Accessed April 10, 2021. http://ubm.opus.hbz-nrw.de/volltexte/2012/3047/.

MLA Handbook (7^th Edition):

Isbert, Simone. “Cellular localization and mechanism of amyloid precursor protein (APP) homodimer formation in an oxidizing environment.” 2012. Web. 10 Apr 2021.

Vancouver:

Isbert S. Cellular localization and mechanism of amyloid precursor protein (APP) homodimer formation in an oxidizing environment. [Internet] [Doctoral dissertation]. Johannes Gutenberg Universität Mainz; 2012. [cited 2021 Apr 10]. Available from: http://ubm.opus.hbz-nrw.de/volltexte/2012/3047/.

Council of Science Editors:

Isbert S. Cellular localization and mechanism of amyloid precursor protein (APP) homodimer formation in an oxidizing environment. [Doctoral Dissertation]. Johannes Gutenberg Universität Mainz; 2012. Available from: http://ubm.opus.hbz-nrw.de/volltexte/2012/3047/

Open Access Theses and Dissertations