subject:(amyloid)

University of Southern California

1. Okada, Alan Kiyoshi. Enhancing and inhibiting diabetic amyloid misfolding.

Degree: PhD, Integrative Biology of Disease, 2016, University of Southern California

URL: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/639571/rec/2381

► The misfolding and aggregation of proteins is associated with some of the most devastating diseases of the modern era, including type 2 diabetes mellitus, Alzheimer… (more)

▼ The misfolding and aggregation of proteins is associated with some of the most devastating diseases of the modern era, including type 2 diabetes mellitus, Alzheimer disease and Parkinson disease. In type 2 diabetes mellitus (T2DM), the misfolding of the 37-amino acid peptide, islet amyloid polypeptide (IAPP), is associated with cytotoxicity of insulin producing β-cells. It is thought that efforts to intervene in the misfolding process will lead to the development of therapeutics for diseases such as T2DM. To facilitate these efforts, it is important to identify conformations of proteins involved in disease-associated misfolding cascades. In this thesis we investigate the misfolding of IAPP using a combination of thioflavin T fluorescence (ThT), circular dichroism (CD), electron paramagnetic resonance spectroscopy (EPR), and transmission electron microscopy (TEM). We find that liposomes loaded with anionic lipids and lipid-like molecules associated with T2DM risk factors (e.g. obesity and plastics exposure), such as phosphatidic acid (PA), oleic acid (OA), a fatty acid, and monobenzylester phthalate (MBzP), a monophthalate ester, dramatically enhance the misfolding of IAPP. Such membrane interactions with IAPP lead to the rapid formation of a membrane-bound and metastable α-helical intermediate that slowly transitions into fibrillar amyloid on the surface of the membrane. Due to the mitochondrial dysfunction seen in T2DM, we also investigated the interaction between the negatively charged cardiolipin (CL), a uniquely mitochondrial lipid and IAPP. We found that CL enhances the misfolding of IAPP in a manner similar to that of PA, OA and MBzP. These data are consistent with the hypothesis that the ability to induce membrane-mediated misfolding of IAPP is a generic trait of negatively charged membranes. This highlights the importance of the α-helical conformation of IAPP as a drug development target since multiple risk factors for T2DM, as well as mitochondria-like membranes, induce misfolding of IAPP through the same α-helical conformer. ❧ We then investigated the ability of two mitochondrial derived peptides (MDPs) to alter the course of IAPP misfolding and found that both MDPs inhibit misfolding by direct, chaperone-like interactions with misfolded amyloid seeds. This chaperone-like activity makes these MDPs exciting new prospects for development as T2DM therapeutics since they provide the opportunity to target key conformations along the misfolding pathway without necessitating atomistic level characterization of the conformers themselves. ❧ Taken together, this work focuses on two key targets along the IAPP misfolding pathway. First, we highlight the importance of the α-helical intermediate of IAPP formed during membrane-mediated misfolding. Second, we characterize two naturally occurring peptides of the MDP family with chaperone-like activities that target misfolded IAPP conformations to prevent propagation by misfolded templates. These studies are a part of larger, ongoing efforts to understand the amyloid… Advisors/Committee Members: Siemer, Ansgar (Committee Chair), Langen, Ralf (Committee Member), Chow, Robert (Committee Member), Chen, Jeannie (Committee Member).

Subjects/Keywords: diabetes; amyloid; islet amyloid polypeptide

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APA (6^th Edition):

Okada, A. K. (2016). Enhancing and inhibiting diabetic amyloid misfolding. (Doctoral Dissertation). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/639571/rec/2381

Chicago Manual of Style (16^th Edition):

Okada, Alan Kiyoshi. “Enhancing and inhibiting diabetic amyloid misfolding.” 2016. Doctoral Dissertation, University of Southern California. Accessed March 08, 2021. http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/639571/rec/2381.

MLA Handbook (7^th Edition):

Okada, Alan Kiyoshi. “Enhancing and inhibiting diabetic amyloid misfolding.” 2016. Web. 08 Mar 2021.

Vancouver:

Okada AK. Enhancing and inhibiting diabetic amyloid misfolding. [Internet] [Doctoral dissertation]. University of Southern California; 2016. [cited 2021 Mar 08]. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/639571/rec/2381.

Council of Science Editors:

Okada AK. Enhancing and inhibiting diabetic amyloid misfolding. [Doctoral Dissertation]. University of Southern California; 2016. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/639571/rec/2381

Florida Atlantic University

2. Lantz, Richard. HUMAN CALCITONIN: AN INVESTIGATION OF AMYLOID FORMATION AND INHIBITION.

Degree: 2020, Florida Atlantic University

URL: http://fau.digital.flvc.org/islandora/object/fau:44433

►

Human calcitonin (hCT) is a peptide hormone that is produced by the thyroid gland where it regulates blood calcium and stimulates bone formation. However, increased… (more)

▼

Human calcitonin (hCT) is a peptide hormone that is produced by the thyroid gland where it regulates blood calcium and stimulates bone formation. However, increased concentrations can cause hCT to aggregate into amyloid fibrils where they can cause cellular toxicity. In this dissertation, we investigated the role of the N-terminal intramolecular disulfide bond, the effects cholesterol derivatives, the inhibitory effects of a group of polyphenolic molecules, and membrane interactions on hCT amyloid formation. To better understand hCT amyloid formation, we investigated the role of the N-terminal intramolecular disulfide bond has on the aggregation kinetics of hCT. Our results demonstrated that the presence of the disulfide bond is key to the formation of the oligomeric nucleus that is needed for amyloid formation. We also investigated the role of cholesterol, cholesterol sulfate, and 3β-[N-(dimethylaminoethane)carbamoyl]-cholesterol (DC-cholesterol) in moderating hCT fibril formation. We showed that cholesterol does not significantly affect hCT fibrillization while high concentrations of cholesterol sulfate has a moderate inhibiting effect. However, DC-cholesterol strongly inhibits hCT fibril formation in a concentration-dependent manner suggesting the role of electrostatic and hydrogen bonding interactions have in moderating the interactivity between hCT and the surface of DC-cholesterol vesicles. We also probed the inhibitory effects of a group of polyphenolic molecules on hCT fibril formation. Our results showed that molecules containing vicinal hydroxyl groups on the phenyl ring effectively inhibits hCT fibril formation though a plausible covalent linkage between the oxidized polyphenol and hCT.

2020

Degree granted: Dissertation (Ph.D.) – Florida Atlantic University, 2020.

Collection: FAU

Advisors/Committee Members: Du, Deguo (Thesis advisor), Florida Atlantic University (Degree grantor), Department of Chemistry and Biochemistry, Charles E. Schmidt College of Science.

Subjects/Keywords: Calcitonin; Amyloid

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APA (6^th Edition):

Lantz, R. (2020). HUMAN CALCITONIN: AN INVESTIGATION OF AMYLOID FORMATION AND INHIBITION. (Thesis). Florida Atlantic University. Retrieved from http://fau.digital.flvc.org/islandora/object/fau:44433

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):

Lantz, Richard. “HUMAN CALCITONIN: AN INVESTIGATION OF AMYLOID FORMATION AND INHIBITION.” 2020. Thesis, Florida Atlantic University. Accessed March 08, 2021. http://fau.digital.flvc.org/islandora/object/fau:44433.

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

MLA Handbook (7^th Edition):

Lantz, Richard. “HUMAN CALCITONIN: AN INVESTIGATION OF AMYLOID FORMATION AND INHIBITION.” 2020. Web. 08 Mar 2021.

Vancouver:

Lantz R. HUMAN CALCITONIN: AN INVESTIGATION OF AMYLOID FORMATION AND INHIBITION. [Internet] [Thesis]. Florida Atlantic University; 2020. [cited 2021 Mar 08]. Available from: http://fau.digital.flvc.org/islandora/object/fau:44433.

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

Council of Science Editors:

Lantz R. HUMAN CALCITONIN: AN INVESTIGATION OF AMYLOID FORMATION AND INHIBITION. [Thesis]. Florida Atlantic University; 2020. Available from: http://fau.digital.flvc.org/islandora/object/fau:44433

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

University of Rochester

3. Easterhoff, David. Characterization of Amyloid Fibrils in Seminal Fluid and Their Interaction With Pathogens.

Degree: PhD, 2013, University of Rochester

URL: http://hdl.handle.net/1802/27256

► Several proteolytic cleavage products of prostatic acid phosphatase and semenogelin have been identified in seminal fluid that are cationic in nature and have amyloidogenic propensity.… (more)

▼ Several proteolytic cleavage products of prostatic acid phosphatase and semenogelin have been identified in seminal fluid that are cationic in nature and have amyloidogenic propensity. These cationic amyloid fibrils, the best described of which is the semen derived enhancer of viral infection (SEVI), have been shown to electrostatically interact with human immunodeficiency virus type 1 (HIV-1) and enhance infection in vitro by allowing virus to associate with the target cells more efficiently. Here, we used biophysical characterization of short self-assembling amyloid fibrils to determine the fibril phenotypes capable of enhancing HIV-1 infection. We also developed new tools to study fibril function. To do this, we screened a targeted library of small molecules in order to identify compounds that efficiently bound to SEVI. Our lead compound bound SEVI and reduced SEVI-mediated enhancement of HIV-1 infection. Additionally, there was enhanced fluorescence from the small molecule when bound to fibrils, suggesting that it may have utility as a novel detection reagent for the identification of SEVI and related fibrils in biological samples. The biological function of semen cationic amyloid fibrils is currently unknown. Since they share characteristics of other antimicrobial peptides, we hypothesized that they may also possess antimicrobial properties. We found that SEVI did not directly inhibit the growth of bacteria, but exerted indirect antimicrobial effects, consistent with a role in promoting bacterial clearance. Specifically, it bound both Gram-positive and Gram-negative bacteria in a charge-dependent manner, promoted their aggregation, facilitated phagocytic uptake by macrophages and neutrophils, enhanced bacterially induced pro-inflammatory cytokine product from macrophage, and protected against vaginal infection in a N. gonorrhoeae murine model. Collectively the data reported in this thesis shed light on the fundamental mechanisms by which cationic amyloid fibrils enhance HIV-1 infection, and suggest that these fibrils act principally by neutralizing charge repulsion between the virus and the host cell, and not by accelerating the sedimentation rate of bound virus particles. Additionally, we identified a novel small molecule that binds efficiently to SEVI and other fibrils, and is also capable of inhibiting SEVImediated enhancement of HIV infection. Finally, we demonstrated that SEVI has indirect antimicrobial activity, suggesting that the natural biologic function(s) of semen derived cationic amyloid fibrils may include a role in the prevention of bacterial infections in the human reproductive tract.

Subjects/Keywords: Amyloid Fibril; Fluorogenic Amyloid Dyes; SEVI; Semen-Associated Amyloid Fibrils

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

APA (6^th Edition):

Easterhoff, D. (2013). Characterization of Amyloid Fibrils in Seminal Fluid and Their Interaction With Pathogens. (Doctoral Dissertation). University of Rochester. Retrieved from http://hdl.handle.net/1802/27256

Chicago Manual of Style (16^th Edition):

Easterhoff, David. “Characterization of Amyloid Fibrils in Seminal Fluid and Their Interaction With Pathogens.” 2013. Doctoral Dissertation, University of Rochester. Accessed March 08, 2021. http://hdl.handle.net/1802/27256.

MLA Handbook (7^th Edition):

Easterhoff, David. “Characterization of Amyloid Fibrils in Seminal Fluid and Their Interaction With Pathogens.” 2013. Web. 08 Mar 2021.

Vancouver:

Easterhoff D. Characterization of Amyloid Fibrils in Seminal Fluid and Their Interaction With Pathogens. [Internet] [Doctoral dissertation]. University of Rochester; 2013. [cited 2021 Mar 08]. Available from: http://hdl.handle.net/1802/27256.

Council of Science Editors:

Easterhoff D. Characterization of Amyloid Fibrils in Seminal Fluid and Their Interaction With Pathogens. [Doctoral Dissertation]. University of Rochester; 2013. Available from: http://hdl.handle.net/1802/27256

Texas State University – San Marcos

4. Campbell, James. Optimization of SDD-AGE as a Method to Study Amyloid Conversion of Human Recombinant Prion Protein.

Degree: MS, Biochemistry, 2014, Texas State University – San Marcos

URL: https://digital.library.txstate.edu/handle/10877/5272

► Many common diseases are caused by amyloid proteins. Amyloid structures are β sheet rich, protease resistant, and can form polydisperse insoluble fibers. Due to these… (more)

Subjects/Keywords: SDD-AGE, Prion, Amyloid; Prion; Amyloid; Amyloid beta-protein; Amyloidosis; Prions; Recombinant proteins

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

APA (6^th Edition):

Campbell, J. (2014). Optimization of SDD-AGE as a Method to Study Amyloid Conversion of Human Recombinant Prion Protein. (Masters Thesis). Texas State University – San Marcos. Retrieved from https://digital.library.txstate.edu/handle/10877/5272

Chicago Manual of Style (16^th Edition):

Campbell, James. “Optimization of SDD-AGE as a Method to Study Amyloid Conversion of Human Recombinant Prion Protein.” 2014. Masters Thesis, Texas State University – San Marcos. Accessed March 08, 2021. https://digital.library.txstate.edu/handle/10877/5272.

MLA Handbook (7^th Edition):

Campbell, James. “Optimization of SDD-AGE as a Method to Study Amyloid Conversion of Human Recombinant Prion Protein.” 2014. Web. 08 Mar 2021.

Vancouver:

Campbell J. Optimization of SDD-AGE as a Method to Study Amyloid Conversion of Human Recombinant Prion Protein. [Internet] [Masters thesis]. Texas State University – San Marcos; 2014. [cited 2021 Mar 08]. Available from: https://digital.library.txstate.edu/handle/10877/5272.

Council of Science Editors:

Campbell J. Optimization of SDD-AGE as a Method to Study Amyloid Conversion of Human Recombinant Prion Protein. [Masters Thesis]. Texas State University – San Marcos; 2014. Available from: https://digital.library.txstate.edu/handle/10877/5272

NSYSU

5. Huang, Huei-Jhen. Influence of chemical conditions on human insulin fibril structure.

Degree: Master, Chemistry, 2013, NSYSU

URL: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0713113-113753

► Many proteins can misfold to form non-native structures and induce aggregation. Previous studies had found that more than 20 kinds of proteins may cause specific… (more)

Subjects/Keywords: alcohol; amyloid; pH; peptide; insulin

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

APA (6^th Edition):

Huang, H. (2013). Influence of chemical conditions on human insulin fibril structure. (Thesis). NSYSU. Retrieved from http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0713113-113753

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):

Huang, Huei-Jhen. “Influence of chemical conditions on human insulin fibril structure.” 2013. Thesis, NSYSU. Accessed March 08, 2021. http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0713113-113753.

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

MLA Handbook (7^th Edition):

Huang, Huei-Jhen. “Influence of chemical conditions on human insulin fibril structure.” 2013. Web. 08 Mar 2021.

Vancouver:

Huang H. Influence of chemical conditions on human insulin fibril structure. [Internet] [Thesis]. NSYSU; 2013. [cited 2021 Mar 08]. Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0713113-113753.

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

Council of Science Editors:

Huang H. Influence of chemical conditions on human insulin fibril structure. [Thesis]. NSYSU; 2013. Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0713113-113753

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

NSYSU

6. Yang, Shu-Wei. Various insulin fibril surface charge distribution studied by Electrostatic Force Microscopy.

Degree: Master, Chemistry, 2012, NSYSU

URL: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0803112-155349

► In this report, electrostatic force microscopy (EFM), zeta-potential analyzer, circular dichroism Spectrophotometer and Fourier transform infrared spectroscopy are used to study the electrostatic property of… (more)

Subjects/Keywords: freezing; salt; EFM; amyloid; insulin

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

APA (6^th Edition):

Yang, S. (2012). Various insulin fibril surface charge distribution studied by Electrostatic Force Microscopy. (Thesis). NSYSU. Retrieved from http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0803112-155349

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):

Yang, Shu-Wei. “Various insulin fibril surface charge distribution studied by Electrostatic Force Microscopy.” 2012. Thesis, NSYSU. Accessed March 08, 2021. http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0803112-155349.

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

MLA Handbook (7^th Edition):

Yang, Shu-Wei. “Various insulin fibril surface charge distribution studied by Electrostatic Force Microscopy.” 2012. Web. 08 Mar 2021.

Vancouver:

Yang S. Various insulin fibril surface charge distribution studied by Electrostatic Force Microscopy. [Internet] [Thesis]. NSYSU; 2012. [cited 2021 Mar 08]. Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0803112-155349.

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

Council of Science Editors:

Yang S. Various insulin fibril surface charge distribution studied by Electrostatic Force Microscopy. [Thesis]. NSYSU; 2012. Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0803112-155349

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

NSYSU

7. Chang, Chiung-Wen. Investigation of the Insulin Amyloid Fibrils Structural Information by Atomic Force Microscope.

Degree: Master, Chemistry, 2011, NSYSU

URL: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0802111-124018

► We study the conformational change of insulin fibril growth from three aspects: the impact of (i) incubation time; (ⅱ) nano-particles; (iii) and ion added. We… (more)

Subjects/Keywords: salt; nanoparticle; AFM; amyloid; Insulin

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APA (6^th Edition):

Chang, C. (2011). Investigation of the Insulin Amyloid Fibrils Structural Information by Atomic Force Microscope. (Thesis). NSYSU. Retrieved from http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0802111-124018

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):

Chang, Chiung-Wen. “Investigation of the Insulin Amyloid Fibrils Structural Information by Atomic Force Microscope.” 2011. Thesis, NSYSU. Accessed March 08, 2021. http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0802111-124018.

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

MLA Handbook (7^th Edition):

Chang, Chiung-Wen. “Investigation of the Insulin Amyloid Fibrils Structural Information by Atomic Force Microscope.” 2011. Web. 08 Mar 2021.

Vancouver:

Chang C. Investigation of the Insulin Amyloid Fibrils Structural Information by Atomic Force Microscope. [Internet] [Thesis]. NSYSU; 2011. [cited 2021 Mar 08]. Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0802111-124018.

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

Council of Science Editors:

Chang C. Investigation of the Insulin Amyloid Fibrils Structural Information by Atomic Force Microscope. [Thesis]. NSYSU; 2011. Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0802111-124018

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

University of Tasmania

8. Hu, Y. Role of amyloid precursor protein in neural stem/progenitor cell proliferation and differentiation.

Degree: 2016, University of Tasmania

URL: https://eprints.utas.edu.au/23030/1/Hu_whole_thesis.pdf

► Alzheimer’s disease (AD) is a progressive neurodegenerative condition that commonly affects people over the age of 65. There are currently no effective treatments which prevent… (more)

▼ Alzheimer’s disease (AD) is a progressive neurodegenerative condition that commonly affects people over the age of 65. There are currently no effective treatments which prevent or delay the progression of AD. The disease is characterized by two major pathological hallmarks in the brain, extracellular amyloid plaques and intracellular neurofibrillary tangles. The β-amyloid protein (Aβ) is the major component of the amyloid plaques and is considered to play a central role in AD pathogenesis. Aβ is produced by proteolytic processing of the amyloid precursor protein (APP). However, the normal function of APP remains unclear despite numerous studies. Understanding the biological function of APP may improve our understanding into the molecular basis of AD pathology. APP expression has been reported to increase in neurons during embryogenesis. In addition, enhanced neurogenesis has been observed in the brains of AD patients and in transgenic mice which overexpress APP. However, other studies have reported impaired neurogenesis in APP transgenic mice. Thus, the studies presented here were aimed at investigating the role of APP in neural stem/progenitor cell (NSPC) proliferation and differentiation. To test the effect of APP on NSPC proliferation, NSPCs derived from human APP overexpressing transgenic (Tg2576) mice and APP knockout (APP KO) mice and their corresponding background strain wild type (WT) mice were cultured in a proliferation medium containing growth factors and NSPC growth was measured. The study found than Tg2576 NSPCs proliferated more rapidly than NSPCs from WT control mice. In contrast, NSPCs derived from APP KO mice proliferated less readily than the corresponding background strain mice. The secreted fragments of APP, Aβ and sAPPα, have been reported to affect neurogenesis. The molecular basis of the effect is uncertain. To examine whether sAPPα or two major isoforms of Aβ, Aβ40 and Aβ42, were responsible for APP - induced NSPC proliferation, the WT NSPCs were grown in proliferation medium containing sAPPα, Aβ40 or Aβ42 and the cell proliferation was measured by examining cell viability. No significant difference in cell viability was found between the non – treatment groups and the groups treated with sAPPα, Aβ40 or Aβ42. Besides, immunodepletion of secreted fragments of APP (sAPPα, Aβ) from Tg2576 conditioned medium did not lower NSPC proliferation, indicating that neither sAPPα nor Aβ contributed to the proliferation effect. To examine whether other secreted factors might be involved in the proliferation effect, the ability of cell conditioned medium to stimulate proliferation was tested. NSPC conditioned medium from Tg2576 cultures was found to increase proliferation while conditioned medium from APP KO cultures was found to have a lower effect on proliferation. The effect on proliferation was found to be due to a secreted factor, cystatin C (CysC), which has previously been reported to promote NSPC proliferation. Immunodepletion of CysC from the Tg2576 conditioned…

Subjects/Keywords: Amyloid; stem; proliferation; differentiation

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APA (6^th Edition):

Hu, Y. (2016). Role of amyloid precursor protein in neural stem/progenitor cell proliferation and differentiation. (Thesis). University of Tasmania. Retrieved from https://eprints.utas.edu.au/23030/1/Hu_whole_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):

Hu, Y. “Role of amyloid precursor protein in neural stem/progenitor cell proliferation and differentiation.” 2016. Thesis, University of Tasmania. Accessed March 08, 2021. https://eprints.utas.edu.au/23030/1/Hu_whole_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):

Hu, Y. “Role of amyloid precursor protein in neural stem/progenitor cell proliferation and differentiation.” 2016. Web. 08 Mar 2021.

Vancouver:

Hu Y. Role of amyloid precursor protein in neural stem/progenitor cell proliferation and differentiation. [Internet] [Thesis]. University of Tasmania; 2016. [cited 2021 Mar 08]. Available from: https://eprints.utas.edu.au/23030/1/Hu_whole_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:

Hu Y. Role of amyloid precursor protein in neural stem/progenitor cell proliferation and differentiation. [Thesis]. University of Tasmania; 2016. Available from: https://eprints.utas.edu.au/23030/1/Hu_whole_thesis.pdf

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

9. Pithadia, Amit S. Using Small Molecules and Peptides as Chemical Tools to Study Metal-Amyloid, Membrane-Amyloid, and Peptide-Amyloid Interactions.

Degree: PhD, Chemistry, 2016, University of Michigan

URL: http://hdl.handle.net/2027.42/120866

► Amyloid proteins are a family a proteins that are characterized by the misfolding an intrinsically disordered monomer subunit into an ordered beta-sheet fibril. Recent evidence… (more)

▼ Amyloid proteins are a family a proteins that are characterized by the misfolding an intrinsically disordered monomer subunit into an ordered beta-sheet fibril. Recent evidence has suggested that the monomer and fibril species are relatively inert; however, aggregates along the misfolding pathway are directly linked to cytotoxicity. It is known that biological cofactors and membranes may play a part in these deleterious events. Specifically metal ions and lipid bilayers may have a role in amyloid-associated toxicity through misregulation of metal ions and generation of oxidative stress with redox active metal ions or disruption of membrane integrity through pore formation and fragmentation of the bilayer. In order to better understand how metal ions and lipid bilayers are involved with amyloid aggregation and toxicity, small molecules can be used as chemical tools. A series of diphenylpropynone derivatives were developed to study the interaction of bifunctional ligands on metal-Aβ aggregation. Both DPP1 and DPP2 showed reactivity toward metal–Aβ species over metal-free Aβ species to different extents. In particular, DPP2, which contains a dimethylamino group, exhibited greater reactivity with metal–Aβ species than DPP1. Small molecules can also be applied as chemical modulators for lipid-associated amyloid aggregation. A curcumin derivative, CurDAc, was developed to investigate the mitigation of hIAPP aggregation in the absence and presence of lipid membrane. CurDAc showed tremendous inhibitory propensity for both lipid-free and lipid-assisted IAPP aggregation in vitro, making it an ideal candidate for further SAR studies. To gain insights into the misfolding pathway and oligomerization of amyloid proteins, the self-assembly of TK9, a nine-residue peptide and its variants were characterized through biophysical, spectroscopic, and simulated studies, and it was confirmed that the structure of these peptides influences their aggregation propensity, hence, mimicking amyloid proteins. This peptide also showed promise as a chemical inhibitor for hIAPP aggregation. Through this work, insights into effective structural scaffold to modify amyloid aggregation in the presence of biological cofactors are understood. Moreover, the discovery of a structural scaffold to monitor oligomer and fibril formation in order to elucidate species along the misfolding pathway has also been made. Advisors/Committee Members: Ramamoorthy, Ayyalusamy (committee member), Fierke, Carol (committee member), Nikolovska-Coleska, Zaneta (committee member), Wolfe, John P (committee member), Ruotolo, Brandon Thomas (committee member).

Subjects/Keywords: Amyloid; small molecule; Chemistry; Science

11 more images…

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APA (6^th Edition):

Pithadia, A. S. (2016). Using Small Molecules and Peptides as Chemical Tools to Study Metal-Amyloid, Membrane-Amyloid, and Peptide-Amyloid Interactions. (Doctoral Dissertation). University of Michigan. Retrieved from http://hdl.handle.net/2027.42/120866

Chicago Manual of Style (16^th Edition):

Pithadia, Amit S. “Using Small Molecules and Peptides as Chemical Tools to Study Metal-Amyloid, Membrane-Amyloid, and Peptide-Amyloid Interactions.” 2016. Doctoral Dissertation, University of Michigan. Accessed March 08, 2021. http://hdl.handle.net/2027.42/120866.

MLA Handbook (7^th Edition):

Pithadia, Amit S. “Using Small Molecules and Peptides as Chemical Tools to Study Metal-Amyloid, Membrane-Amyloid, and Peptide-Amyloid Interactions.” 2016. Web. 08 Mar 2021.

Vancouver:

Pithadia AS. Using Small Molecules and Peptides as Chemical Tools to Study Metal-Amyloid, Membrane-Amyloid, and Peptide-Amyloid Interactions. [Internet] [Doctoral dissertation]. University of Michigan; 2016. [cited 2021 Mar 08]. Available from: http://hdl.handle.net/2027.42/120866.

Council of Science Editors:

Pithadia AS. Using Small Molecules and Peptides as Chemical Tools to Study Metal-Amyloid, Membrane-Amyloid, and Peptide-Amyloid Interactions. [Doctoral Dissertation]. University of Michigan; 2016. Available from: http://hdl.handle.net/2027.42/120866

University of Manchester

10. Howard, Daniel. The role of the cytoskeleton in Alzheimer’s disease: a Drosophila perspective.

Degree: 2016, University of Manchester

URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:300556

► Alzheimer’s disease (AD) pathogenesis is likely to be caused by dysfunction of two neuronal proteins, amyloid-beta (Aβ) and tau. Whilst excellent in vivo assays have… (more)

Subjects/Keywords: drosophila; neurodegeneration; amyloid; tau

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

APA (6^th Edition):

Howard, D. (2016). The role of the cytoskeleton in Alzheimer’s disease: a Drosophila perspective. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:300556

Chicago Manual of Style (16^th Edition):

Howard, Daniel. “The role of the cytoskeleton in Alzheimer’s disease: a Drosophila perspective.” 2016. Doctoral Dissertation, University of Manchester. Accessed March 08, 2021. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:300556.

MLA Handbook (7^th Edition):

Howard, Daniel. “The role of the cytoskeleton in Alzheimer’s disease: a Drosophila perspective.” 2016. Web. 08 Mar 2021.

Vancouver:

Howard D. The role of the cytoskeleton in Alzheimer’s disease: a Drosophila perspective. [Internet] [Doctoral dissertation]. University of Manchester; 2016. [cited 2021 Mar 08]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:300556.

Council of Science Editors:

Howard D. The role of the cytoskeleton in Alzheimer’s disease: a Drosophila perspective. [Doctoral Dissertation]. University of Manchester; 2016. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:300556

University of Manchester

11. Noble, Elizabeth. The molecular mechanisms linking amyloid-beta, the prion protein and tau in Alzheimer's disease.

Degree: 2017, University of Manchester

URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:306712

► Several lines of evidence suggest that the expression of the cellular prion protein (PrPC) is altered with age and in sporadic Alzheimer’s disease, however, published… (more)

▼ Several lines of evidence suggest that the expression of the cellular prion protein (PrPC) is altered with age and in sporadic Alzheimer’s disease, however, published results have been contradictory. Furthermore, a relationship between the expression of PrPC and Tau has started to emerge. We have revealed a specific relationship between the expression of PrPC and Tau in neuroblastoma cell lines and transgenic mouse models. In addition, we identified that the expression levels of PrPC are reduced in multiple brain regions following the progression of sporadic Alzheimer’s disease. Furthermore, the reduction in PrPC expression significantly correlated with the reduction in Tau expression and coincided with an increase in Tau pathology. In addition, data from neuroblastoma cell lines implicated the glycosylphosphatidylinositol (GPI)-anchor and in part the localisation of PrPC to lipid rafts in mediating these alterations to Tau. We hypothesise that the reduction in PrPC expression reflects a primary mechanism in Alzheimer’s disease pathogenesis and indirectly triggers the reduction in Tau expression which subsequently contributes to neuronal destabilisation and disruption to neuronal function. Soluble oligomeric forms of amyloid-beta are the primary pathogenic species in Alzheimer’s disease and strongly correlate with the presence and severity of cognitive decline. PrPC acts as a high affinity neuronal receptor for amyloid-beta oligomers and triggers pathogenic signaling cascades which induce synaptic impairment and further exacerbate neuronal destabilisation. We demonstrated that Flotillin-1 and the lipid raft localisation of PrPC are essential for the binding of amyloid-beta oligomers to PrPC. Furthermore, the metabotropic glutamate receptor, mGluR5 plays a pivotal role in the aberrant signaling of PrPC, and this PrPC/mGluR5 complex provides a mechanistic link between extracellular amyloid-beta oligomers and intracellular Tau phosphorylation, by Fyn kinase, Pyk2 and possibly by inactivation of the protein phosphatase, PP2A. Considering there is now strong evidence that Tau is the mediator of amyloid-beta induced toxicity, the reduction in Tau levels mediated by PrPC may be a protective mechanism. amyloid-beta oligomers interact with a multitude of neuronal receptors in addition to PrPC. It is likely that activation of multiple receptor complexes and signalling cascades are responsible for synaptic impairment and Tau phosphorylation induced by amyloid-beta, however, these complexes remain to be fully determined. Investigating amyloid-beta oligomer induced Tau phosphorylation in vitro has proven challenging, however, we suggest that a functional, mature, neuronal model is necessary to induce the complex mechanisms linking extracellular amyloid-beta oligomers and the phosphorylation of intracellular Tau. A greater understanding of the complex relationship between amyloid-beta, PrPC and Tau will aid in our understanding of the molecular mechanisms underlying Alzheimer’s disease and in the discovery of novel therapeutic… Advisors/Committee Members: PICKERING-BROWN, STUART SM, Pickering-Brown, Stuart, Hooper, Nigel.

Subjects/Keywords: Alzheimers; Amyloid; Prion protein; Tau

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

APA (6^th Edition):

Noble, E. (2017). The molecular mechanisms linking amyloid-beta, the prion protein and tau in Alzheimer's disease. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:306712

Chicago Manual of Style (16^th Edition):

Noble, Elizabeth. “The molecular mechanisms linking amyloid-beta, the prion protein and tau in Alzheimer's disease.” 2017. Doctoral Dissertation, University of Manchester. Accessed March 08, 2021. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:306712.

MLA Handbook (7^th Edition):

Noble, Elizabeth. “The molecular mechanisms linking amyloid-beta, the prion protein and tau in Alzheimer's disease.” 2017. Web. 08 Mar 2021.

Vancouver:

Noble E. The molecular mechanisms linking amyloid-beta, the prion protein and tau in Alzheimer's disease. [Internet] [Doctoral dissertation]. University of Manchester; 2017. [cited 2021 Mar 08]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:306712.

Council of Science Editors:

Noble E. The molecular mechanisms linking amyloid-beta, the prion protein and tau in Alzheimer's disease. [Doctoral Dissertation]. University of Manchester; 2017. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:306712

Cornell University

12. Anderson, Valerie. Alpha-Synuclein And Enhanced Green Fluorescent Protein In Trifluoroethanol: Protective Factors Oppose Protein Aggregation.

Degree: PhD, Physics, 2011, Cornell University

URL: http://hdl.handle.net/1813/30736

► Protein aggregation, leading to the formation of amyloid fibrils, is associated with many human diseases, including Parkinson's disease, Alzheimer's disease and type II diabetes. 2,2,2-trifluoroethanol… (more)

▼ Protein aggregation, leading to the formation of amyloid fibrils, is associated with many human diseases, including Parkinson's disease, Alzheimer's disease and type II diabetes. 2,2,2-trifluoroethanol (TFE) is frequently used to induce amyloid conversion in biophysical studies, but the mechanisms underlying TFE-induced fibrillization are not yet well understood. We have measured secondary structural changes of the Parkinson's disease-associated protein [alpha]-synuclein ([alpha]S), and have discovered that TFE-induced aggregation is correlated with population of a partially structured state of the monomer protein. By investigating the pH- and temperaturedependences of the conformational transitions, we find evidence that loss of proteinsolvent interactions drives both the structural changes and the fibril production. Furthermore, we used enhanced green fluorescent protein (EGFP) as a model system to examine the effects of sequence and tertiary structure in TFE-induced aggregation, and found that the behavior of acid-denatured EGFP is qualitatively similar to [alpha]S, while tertiary structure impedes aggregation. We conclude that initiation of protein aggregation in solutions containing TFE involves overcoming multiple protective factors, rather than stabilization of specific structural elements. We identify three distinct structural states that contribute to the circular dichroism spectra of [alpha]S variants and acid-denatured EGFP. For both types of proteins, a partially [alpha]-helical conformation is populated at moderate TFE concentrations where aggregation is enhanced. The TFE-induced [alpha]S fibrils are [beta]-sheet-rich, flexible, helical structures, while the EGFP aggregates are flexible, uniform-width fibrils. At low (<10-15% v/v) TFE, the [alpha]S variants and acid-denatured EGFP undergo loss of polyproline-II structure, which is suggestive of reduced protein-water interactions. At higher TFE, preferential solvation leads to TFE coating of the proteins, stabilizing [alpha]-helical structures. The temperature response of [alpha]S reveals distinct behavior for proteins in water-like vs. TFE-like local environments. Moreover, the intermediate-TFE conformations appear to be invariant with respect to temperature and pH, which indicates that the proteins experience reduced solvent interactions at moderate [TFE]. Our results suggest that TFE reduces solvation barriers in aggregation reactions. However, aggregation pathway selection may depend on details of protein structure, and the protein sequence affects the TFE concentrations required for dehydration-driven fibrillization. Advisors/Committee Members: Webb, Watt Wetmore (chair), Nicholson, Linda K (committee member), Sethna, James Patarasp (committee member).

Subjects/Keywords: trifluoroethanol; amyloid; protein aggregation

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

APA (6^th Edition):

Anderson, V. (2011). Alpha-Synuclein And Enhanced Green Fluorescent Protein In Trifluoroethanol: Protective Factors Oppose Protein Aggregation. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/30736

Chicago Manual of Style (16^th Edition):

Anderson, Valerie. “Alpha-Synuclein And Enhanced Green Fluorescent Protein In Trifluoroethanol: Protective Factors Oppose Protein Aggregation.” 2011. Doctoral Dissertation, Cornell University. Accessed March 08, 2021. http://hdl.handle.net/1813/30736.

MLA Handbook (7^th Edition):

Anderson, Valerie. “Alpha-Synuclein And Enhanced Green Fluorescent Protein In Trifluoroethanol: Protective Factors Oppose Protein Aggregation.” 2011. Web. 08 Mar 2021.

Vancouver:

Anderson V. Alpha-Synuclein And Enhanced Green Fluorescent Protein In Trifluoroethanol: Protective Factors Oppose Protein Aggregation. [Internet] [Doctoral dissertation]. Cornell University; 2011. [cited 2021 Mar 08]. Available from: http://hdl.handle.net/1813/30736.

Council of Science Editors:

Anderson V. Alpha-Synuclein And Enhanced Green Fluorescent Protein In Trifluoroethanol: Protective Factors Oppose Protein Aggregation. [Doctoral Dissertation]. Cornell University; 2011. Available from: http://hdl.handle.net/1813/30736

University of Manchester

13. Moreth, Jens. Characterisation of different amyloid-ß aggregates in Alzheimer's Disease.

Degree: 2012, University of Manchester

URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:164717

► Alzheimer’s disease (AD) is the most common form of dementia, with more than 25 million people worldwide suffering this progressive intellectual failure. The disease was… (more)

▼ Alzheimer’s disease (AD) is the most common form of dementia, with more than 25 million people worldwide suffering this progressive intellectual failure. The disease was first described by the German psychiatrist, Alois Alzheimer in 1907, and is characterised by the appearance of proteinaceous depositions (first isolated in 1984), which are comprised of insoluble amyloid-ß (Aß)-aggregates. Aβ is derived from the β-amyloid precursor protein from which it is generated by the action of two proteases. Initially it was assumed that the insoluble amyloid fibrils, which were easily detectable, mediated the observed toxicity although it was recognised that amyloid plaque number did not correlate well with the severity of dementia. However, further studies with synthetic and human-derived Aß provided strong evidence that soluble prefibrillar aggregates of Aß mediated the synaptic failure and loss of cognitive performance. In 2008 genetic evidence showed that the presence of soluble Aß-oligomers is sufficient to cause an AD-like dementia, which centres the oligomeric Aβ as the probable effector of synapse loss.Although a variety of assemblies have been described their meta-stability and technical limitations caused a controversial debate about aggregate related pathogenesis. Thus, this study aimed to establish a structure-activity relationship comparing different synthetic Aß-aggregates using biophysical methods to follow aggregation and to assess morphology, absolute MW and meta-stability of monomeric, oligomeric, protofibrillar and fibrillar Aß. However, interference with the aggregate equilibrium, by changing the ionic environment, can cause structural conversion of Aß-aggregates. Therefore, different Aß-aggregates were only compared in short-termed physiological settings i.e. neuronal binding and hippocampal neurotransmission. Herein, only prefibrillar aggregates bound to neurons and differentially impaired hippocampal neurotransmission either by inhibition of basal neurotransmission or NMDA-dependent long-term potentiation. In addition, changing the ionic environment provoked a structural conversion, which also changed the pathogenic mode of action. This study provides experimental evidence that different soluble Aß-aggregates are highly potent synaptotoxins, impairing neurotransmission by different mechanisms. Furthermore, solution-based biophysical characterisation and acute biological paradigms are crucial for differential characterisation of Aß-aggregates revealing that virtually similar aggregates can have opponent pathogenic effects; thus, morphology only does not explain observed pathogenicity. Advisors/Committee Members: Edwards, Gillian.

Subjects/Keywords: Alzheimer's Disease; Amyloid beta

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

APA (6^th Edition):

Moreth, J. (2012). Characterisation of different amyloid-ß aggregates in Alzheimer's Disease. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:164717

Chicago Manual of Style (16^th Edition):

Moreth, Jens. “Characterisation of different amyloid-ß aggregates in Alzheimer's Disease.” 2012. Doctoral Dissertation, University of Manchester. Accessed March 08, 2021. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:164717.

MLA Handbook (7^th Edition):

Moreth, Jens. “Characterisation of different amyloid-ß aggregates in Alzheimer's Disease.” 2012. Web. 08 Mar 2021.

Vancouver:

Moreth J. Characterisation of different amyloid-ß aggregates in Alzheimer's Disease. [Internet] [Doctoral dissertation]. University of Manchester; 2012. [cited 2021 Mar 08]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:164717.

Council of Science Editors:

Moreth J. Characterisation of different amyloid-ß aggregates in Alzheimer's Disease. [Doctoral Dissertation]. University of Manchester; 2012. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:164717

University of Toronto

14. Zukotynski, Katherine. Associations of Amyloid Deposition and FDG Uptake in Aging and Cognitively Impaired Elders With and Without Moderate to Severe Periventricular White Matter Hyperintensities Using Simple Machine Learning Techniques.

Degree: PhD, 2020, University of Toronto

URL: http://hdl.handle.net/1807/101041

► Abstract Background: Cerebral small vessel disease (SVD) often coexists with Alzheimer’s Disease (AD), but subjects with significant SVD were usually considered mixed disease and excluded… (more)

▼ Abstract Background: Cerebral small vessel disease (SVD) often coexists with Alzheimer’s Disease (AD), but subjects with significant SVD were usually considered mixed disease and excluded from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and other international cohorts. We use 2 machine learning algorithms (random forests (RFs) and K-means clustering) and 2 radiopharmaceuticals (18F-Florbetabir and 18F-FDG) to study associations of periventricular white matter hyperintensity (pvWMH), amyloid deposition and 18F-FDG uptake in aging and cognitively impaired elders. Methods: A multi-center, observational, prospective cohort study was designed to acquire data in subjects with significant pvWMH. Baseline data from the first 57 subjects recruited through tertiary memory clinics or stroke prevention clinics formed the basis for analysis. All subjects had a 3T MRI, 18F-Florbetabir PET and neurological evaluation; 18F-FDG PET was available in 55. A matched cohort of 57 subjects with minimal pvWMH was derived from ADNI. PETs were interpreted by 2 dual certified radiologists/ nuclear medicine physicians with MIM software (MIM Software Inc, Cleveland, Ohio) and processed to obtain quantitative data in regions of interest (ROIs). Algorithms programmed in MATLAB were used to classify 18F-Florbetabir PET as positive or negative for amyloid deposition, suggest ROIs for classification, and study associations with pvWMH. Discussion: This work complements current data on associations of amyloid, 18F-FDG and pvWMH. RFs (supervised) and K-means clustering (unsupervised) had similar classification accuracy for 18F-Florbetabir PET with clinical interpretation as the gold standard. ROIs for classification were, most commonly: the left posterior cingulate, left precuneus and left middle fontal gyrus; key nodes of the default node network, where amyloid deposition preferentially begins in the brain of patients with AD. Subjects with significant pvWMH had slightly more amyloid deposition across a spectrum of ROIs compared with their matched ADNI cohort. 18F-FDG uptake was slightly higher in several cortical ROIs with lower uptake in the basal ganglia. Possibly these findings can be explained by poor amyloid clearance related to venous collagenosis in subjects with significant pvWMH coupled with metabolic compensation. Future research will include evaluation of 2-year follow-up, correlation of PET with MRI, neurological assessment and ApoE4 status in the full cohort of subjects. Advisors/Committee Members: Black, Sandra E, Biomedical Engineering.

Subjects/Keywords: Amyloid; Dementia; PET; 0541

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

APA (6^th Edition):

Zukotynski, K. (2020). Associations of Amyloid Deposition and FDG Uptake in Aging and Cognitively Impaired Elders With and Without Moderate to Severe Periventricular White Matter Hyperintensities Using Simple Machine Learning Techniques. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/101041

Chicago Manual of Style (16^th Edition):

Zukotynski, Katherine. “Associations of Amyloid Deposition and FDG Uptake in Aging and Cognitively Impaired Elders With and Without Moderate to Severe Periventricular White Matter Hyperintensities Using Simple Machine Learning Techniques.” 2020. Doctoral Dissertation, University of Toronto. Accessed March 08, 2021. http://hdl.handle.net/1807/101041.

MLA Handbook (7^th Edition):

Zukotynski, Katherine. “Associations of Amyloid Deposition and FDG Uptake in Aging and Cognitively Impaired Elders With and Without Moderate to Severe Periventricular White Matter Hyperintensities Using Simple Machine Learning Techniques.” 2020. Web. 08 Mar 2021.

Vancouver:

Zukotynski K. Associations of Amyloid Deposition and FDG Uptake in Aging and Cognitively Impaired Elders With and Without Moderate to Severe Periventricular White Matter Hyperintensities Using Simple Machine Learning Techniques. [Internet] [Doctoral dissertation]. University of Toronto; 2020. [cited 2021 Mar 08]. Available from: http://hdl.handle.net/1807/101041.

Council of Science Editors:

Zukotynski K. Associations of Amyloid Deposition and FDG Uptake in Aging and Cognitively Impaired Elders With and Without Moderate to Severe Periventricular White Matter Hyperintensities Using Simple Machine Learning Techniques. [Doctoral Dissertation]. University of Toronto; 2020. Available from: http://hdl.handle.net/1807/101041

University of Manchester

15. Moreth, Jens. Characterisation of different amyloid-ß aggregates in Alzheimer's disease.

Degree: PhD, 2012, University of Manchester

URL: https://www.research.manchester.ac.uk/portal/en/theses/characterisation-of-different-amyloidss-aggregates-in-alzheimers-disease(88c7e7d8-dd08-4559-aa20-40f26950f0d5).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.632161

► Alzheimer’s disease (AD) is the most common form of dementia, with more than 25 million people worldwide suffering this progressive intellectual failure. The disease was… (more)

▼ Alzheimer’s disease (AD) is the most common form of dementia, with more than 25 million people worldwide suffering this progressive intellectual failure. The disease was first described by the German psychiatrist, Alois Alzheimer in 1907, and is characterised by the appearance of proteinaceous depositions (first isolated in 1984), which are comprised of insoluble amyloid-ß (Aß)-aggregates. Aβ is derived from the β-amyloid precursor protein from which it is generated by the action of two proteases. Initially it was assumed that the insoluble amyloid fibrils, which were easily detectable, mediated the observed toxicity although it was recognised that amyloid plaque number did not correlate well with the severity of dementia. However, further studies with synthetic and human-derived Aß provided strong evidence that soluble prefibrillar aggregates of Aß mediated the synaptic failure and loss of cognitive performance. In 2008 genetic evidence showed that the presence of soluble Aß-oligomers is sufficient to cause an AD-like dementia, which centres the oligomeric Aβ as the probable effector of synapse loss. Although a variety of assemblies have been described their meta-stability and technical limitations caused a controversial debate about aggregate related pathogenesis. Thus, this study aimed to establish a structure-activity relationship comparing different synthetic Aß-aggregates using biophysical methods to follow aggregation and to assess morphology, absolute MW and meta-stability of monomeric, oligomeric, protofibrillar and fibrillar Aß. However, interference with the aggregate equilibrium, by changing the ionic environment, can cause structural conversion of Aß-aggregates. Therefore, different Aß-aggregates were only compared in short-termed physiological settings i.e. neuronal binding and hippocampal neurotransmission. Herein, only prefibrillar aggregates bound to neurons and differentially impaired hippocampal neurotransmission either by inhibition of basal neurotransmission or NMDA-dependent long-term potentiation. In addition, changing the ionic environment provoked a structural conversion, which also changed the pathogenic mode of action. This study provides experimental evidence that different soluble Aß-aggregates are highly potent synaptotoxins, impairing neurotransmission by different mechanisms. Furthermore, solution-based biophysical characterisation and acute biological paradigms are crucial for differential characterisation of Aß-aggregates revealing that virtually similar aggregates can have opponent pathogenic effects; thus, morphology only does not explain observed pathogenicity.

Subjects/Keywords: 616.8; Alzheimer's Disease; Amyloid beta

Record Details Similar Records Cite « Share

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

APA (6^th Edition):

Moreth, J. (2012). Characterisation of different amyloid-ß aggregates in Alzheimer's disease. (Doctoral Dissertation). University of Manchester. Retrieved from https://www.research.manchester.ac.uk/portal/en/theses/characterisation-of-different-amyloidss-aggregates-in-alzheimers-disease(88c7e7d8-dd08-4559-aa20-40f26950f0d5).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.632161

Chicago Manual of Style (16^th Edition):

Moreth, Jens. “Characterisation of different amyloid-ß aggregates in Alzheimer's disease.” 2012. Doctoral Dissertation, University of Manchester. Accessed March 08, 2021. https://www.research.manchester.ac.uk/portal/en/theses/characterisation-of-different-amyloidss-aggregates-in-alzheimers-disease(88c7e7d8-dd08-4559-aa20-40f26950f0d5).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.632161.

MLA Handbook (7^th Edition):

Moreth, Jens. “Characterisation of different amyloid-ß aggregates in Alzheimer's disease.” 2012. Web. 08 Mar 2021.

Vancouver:

Moreth J. Characterisation of different amyloid-ß aggregates in Alzheimer's disease. [Internet] [Doctoral dissertation]. University of Manchester; 2012. [cited 2021 Mar 08]. Available from: https://www.research.manchester.ac.uk/portal/en/theses/characterisation-of-different-amyloidss-aggregates-in-alzheimers-disease(88c7e7d8-dd08-4559-aa20-40f26950f0d5).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.632161.

Council of Science Editors:

Moreth J. Characterisation of different amyloid-ß aggregates in Alzheimer's disease. [Doctoral Dissertation]. University of Manchester; 2012. Available from: https://www.research.manchester.ac.uk/portal/en/theses/characterisation-of-different-amyloidss-aggregates-in-alzheimers-disease(88c7e7d8-dd08-4559-aa20-40f26950f0d5).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.632161

University of Melbourne

16. SAHATHEVAN, RAMESH. Beta amyloid deposition in infarct and peri-infarct areas assessed using 11C Pittsburg Compound B and positron emission tomography.

Degree: 2012, University of Melbourne

URL: http://hdl.handle.net/11343/37807

► Introduction: Alzheimer’s disease (AD) and vascular cognitive impairment (VCI) are the most common forms of dementia. There is epidemiological evidence that vascular risk factors are… (more)

▼ Introduction: Alzheimer’s disease (AD) and vascular cognitive impairment (VCI) are the most common forms of dementia. There is epidemiological evidence that vascular risk factors are associated with an increased risk of developing both AD and VCI. The risk conferred by these vascular factors is independent of their risk of increasing stroke. Approximately 30% of stroke survivors develop dementia and as many as 50% of them may have mixed pathology of AD and VCI. The histopathological confirmation of the AD/VCI overlap suggests that the two conditions may form opposing ends of a spectrum of disease. It also supports the theory that acute and/or chronic ischaemia factor in the pathogenesis of AD. The pathological hallmark of AD is cerebral amyloid (Aβ) deposited mainly as extracellular neuritic plaque or in the wall of leptomeningeal vessels. Advances in positron emission tomography (PET) now allow for in vivo imaging of Aβ. The aim of this study is to determine the immediate and long-term effects of an acute stroke on Aβ deposition. It also aims to assess the influence of vascular disease on Aβ. Methods: Eligible patients admitted with ischaemic stroke underwent an MRI or CT brain to determine stroke characteristics and 11C-PiB-PET scan to enable semi-quantitative estimation of Aβ. Forty-eight stroke patients were included in the analyses and compared against an equal number of controls. Repeat PET scans were performed at intervals ranging from 2 weeks to 18 months. The PET scans were analysed using standard uptake value ratios (SUVR) calculated for the whole brain, the cerebral hemisphere affected by stroke and stroke specific regions. The values were compared to similar SUVR calculated using normal controls or from stroke-free areas in the brain of patients. These values were then compared to determine the immediate effect of stroke in a cross-sectional analysis of the data. Subsequent scans were re-analysed to determine the delayed effects in longitudinal analyses of the data. The effects of vascular risk factors, severity of white matter lesions (WML), stroke type and atherosclerosis were also analysed to determine their influence of Aβ deposition. Results: The overall SUVR of a stroke affected brain does not increase following an infarct when compared to stroke-free controls. However, an increase was noted in the SUVR of the stroke-affected hemisphere and in the region surrounding the stroke when compared to the stroke-free contralateral region in the same patient. This increase in stroke region especially was striking on visual assessment of some PET scans. However, the increase in both stroke-affected hemisphere and the stroke region did not reach statistical significance. When the 11C-PiB-PET was repeated, it was found that the SUVR decreased significantly. This suggested that the initial increase was caused by a transient and reversible process. The most likely explanation for the observation was extravasation of…

Subjects/Keywords: stroke; amyloid; 11C-PiB-PET

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

APA (6^th Edition):

SAHATHEVAN, R. (2012). Beta amyloid deposition in infarct and peri-infarct areas assessed using 11C Pittsburg Compound B and positron emission tomography. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/37807

Chicago Manual of Style (16^th Edition):

SAHATHEVAN, RAMESH. “Beta amyloid deposition in infarct and peri-infarct areas assessed using 11C Pittsburg Compound B and positron emission tomography.” 2012. Doctoral Dissertation, University of Melbourne. Accessed March 08, 2021. http://hdl.handle.net/11343/37807.

MLA Handbook (7^th Edition):

SAHATHEVAN, RAMESH. “Beta amyloid deposition in infarct and peri-infarct areas assessed using 11C Pittsburg Compound B and positron emission tomography.” 2012. Web. 08 Mar 2021.

Vancouver:

SAHATHEVAN R. Beta amyloid deposition in infarct and peri-infarct areas assessed using 11C Pittsburg Compound B and positron emission tomography. [Internet] [Doctoral dissertation]. University of Melbourne; 2012. [cited 2021 Mar 08]. Available from: http://hdl.handle.net/11343/37807.

Council of Science Editors:

SAHATHEVAN R. Beta amyloid deposition in infarct and peri-infarct areas assessed using 11C Pittsburg Compound B and positron emission tomography. [Doctoral Dissertation]. University of Melbourne; 2012. Available from: http://hdl.handle.net/11343/37807

University of Melbourne

17. JOHANSSEN, TIMOTHY. The Role of metals and Aβ in excitotoxicity and Alzheimer’s disease.

Degree: 2015, University of Melbourne

URL: http://hdl.handle.net/11343/55550

► Background: N-methyl-d-aspartate receptors (NMDARs) are ionotropic channels gated by the excitatory amino acid, glutamate. They play an essential role in synaptic plasticity, enhancing synaptic signal… (more)

▼ Background: N-methyl-d-aspartate receptors (NMDARs) are ionotropic channels gated by the excitatory amino acid, glutamate. They play an essential role in synaptic plasticity, enhancing synaptic signal strength through long-term potentiation (LTP), a process thought to underlie learning and memory. At the synapse, NMDARs mediate neuroprotective signaling pathways including the regulation of calcineurin activity and inhibition of glycogen synthase kinase (GSK3). Under pathological conditions the prolonged and enhanced exposure of NMDARs to glutamate results in an excessive flux of calcium (Ca2+) into the cell. This triggers a range of responses resulting in cell death, including increased oxidative stress, inappropriate activation of proteases such as calpain, dysregulation of Ca2+- related pathways, mitochondrial damage and an apoptotic cascade. This process, termed excitotoxicity, contributes significantly to the acute neurodegeneration in ischemia and traumatic brain injury (TBI) and is believed to underlie the chronic neurodegeneration in Huntington’s disease (HD) and more recently, Alzheimer’s disease (AD). Alzheimer’s disease (AD) is characterised by progressive cognitive impairment resulting from synaptic degeneration and neuronal loss. A proposed key event in its aetiology is the formation of oligomeric species of the beta amyloid (Aβ) peptide. Recent work has demonstrated that the soluble Aβ oligomers induce excessive calcium influx across the cell membrane resulting in neuronal death by excitotoxicity. It is believed these toxic species of Aβ oligmomerise in the synaptic cleft between neurons in the hippocampus due to high levels of zinc and copper. These metals are released upon NMDAR activity from the pre- and post-synapse, respectively and can bind Aβ, increasing its rate of oligomerisation. Subsequent excitotoxic interactions between Aβ and NMDARs are copper (Cu2+)-dependent. In contrast, Cu2+ is also neuroprotective against excitotoxicity demonstrating the crucial role of metal homeostasis in specific regions of the brain affected by neurodegenerative diseases. Objectives: This PhD project has sought to determine the contribution of metals in excitotoxicity and whether modulating their levels could provide a mechanism to protect against this form of cell death. As excitotoxicity is strongly implicated in the aetiology of Alzheimer’s disease subsequent research aimed to describe the involvement of excitotoxicity in Aβ-mediated cell death in cortical neural model and to establish whether metals played a necessary role in this process. The final goal of the research presented here was the development of a neural-based assay, which could be employed to screen various forms of Aβ to detect more toxic forms of the peptide. Results: In experiments with the metal chaperone PBT2, a therapeutic in clinical trials for chronic neurodegenerative diseases, neurons…

Subjects/Keywords: Alzheimer's disease; beta amyloid; excitotoxicity

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APA (6^th Edition):

JOHANSSEN, T. (2015). The Role of metals and Aβ in excitotoxicity and Alzheimer’s disease. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/55550

Chicago Manual of Style (16^th Edition):

JOHANSSEN, TIMOTHY. “The Role of metals and Aβ in excitotoxicity and Alzheimer’s disease.” 2015. Doctoral Dissertation, University of Melbourne. Accessed March 08, 2021. http://hdl.handle.net/11343/55550.

MLA Handbook (7^th Edition):

JOHANSSEN, TIMOTHY. “The Role of metals and Aβ in excitotoxicity and Alzheimer’s disease.” 2015. Web. 08 Mar 2021.

Vancouver:

JOHANSSEN T. The Role of metals and Aβ in excitotoxicity and Alzheimer’s disease. [Internet] [Doctoral dissertation]. University of Melbourne; 2015. [cited 2021 Mar 08]. Available from: http://hdl.handle.net/11343/55550.

Council of Science Editors:

JOHANSSEN T. The Role of metals and Aβ in excitotoxicity and Alzheimer’s disease. [Doctoral Dissertation]. University of Melbourne; 2015. Available from: http://hdl.handle.net/11343/55550

University of Southern California

18. Cervantes Cortes, Silvia A. Structural characterization of the functional amyloid Orb2A using EPR spectroscopy.

Degree: MS, Biochemistry and Molecular Biology, 2015, University of Southern California

URL: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/583308/rec/6120

► Functional amyloids are responsible for a variety of physiological processes in a diverse range of organisms. In humans, Pmel17 is involved in the synthesis of… (more)

Subjects/Keywords: functional amyloid; Orb2A; EPR spectroscopy

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APA (6^th Edition):

Cervantes Cortes, S. A. (2015). Structural characterization of the functional amyloid Orb2A using EPR spectroscopy. (Masters Thesis). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/583308/rec/6120

Chicago Manual of Style (16^th Edition):

Cervantes Cortes, Silvia A. “Structural characterization of the functional amyloid Orb2A using EPR spectroscopy.” 2015. Masters Thesis, University of Southern California. Accessed March 08, 2021. http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/583308/rec/6120.

MLA Handbook (7^th Edition):

Cervantes Cortes, Silvia A. “Structural characterization of the functional amyloid Orb2A using EPR spectroscopy.” 2015. Web. 08 Mar 2021.

Vancouver:

Cervantes Cortes SA. Structural characterization of the functional amyloid Orb2A using EPR spectroscopy. [Internet] [Masters thesis]. University of Southern California; 2015. [cited 2021 Mar 08]. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/583308/rec/6120.

Council of Science Editors:

Cervantes Cortes SA. Structural characterization of the functional amyloid Orb2A using EPR spectroscopy. [Masters Thesis]. University of Southern California; 2015. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/583308/rec/6120

University of Hawaii – Manoa

19. Lawrence, James Le Marchant. N-terminal beta amyloid fragments regulate nicotinic acetylcholine receptors.

Degree: 2015, University of Hawaii – Manoa

URL: http://hdl.handle.net/10125/101105

►

Ph.D. University of Hawaii at Manoa 2014.

Soluble β-amyloid (Aβ) has been shown to regulate both presynaptic Ca2+ and synaptic plasticity. In particular picomolar concentrations… (more)

▼

Ph.D. University of Hawaii at Manoa 2014.

Soluble β-amyloid (Aβ) has been shown to regulate both presynaptic Ca2+ and synaptic plasticity. In particular picomolar concentrations of Aβ were found to have an agonist-like action on presynaptic nicotinic receptors and to augment long-term potentiation (LTP) in a manner dependent upon nicotinic receptors. Here we have found that a functional N-terminal domain containing two histidine residues exists within Aβ that accounts for its agonist-like activity. This sequence corresponds to an N-terminal fragment generated by the combined action of α-and β-secretases, and a resident carboxypeptidase. The N-terminal Aβ fragment is present in the brains and CSF of healthy adults as well as Alzheimer's patients. Unlike full-length Aβ, the N-terminal Aβ fragment is monomeric and nontoxic. In Ca2+ imaging studies using a model reconstituted rodent neuroblastoma cell line and isolated mouse hippocampal nerve terminals, the N-terminal Aβ fragment proved to be highly potent and more effective than full-length Aβ in its agonist-like action on nicotinic receptors. In addition, the N-terminal Aβ fragment augmented theta burst-induced post-tetanic potentiation and LTP in mouse hippocampal slices. The N-terminal Aβ fragment also rescued LTP inhibited by elevated levels of full-length Aβ. Contextual fear conditioning was also strongly augmented following bilateral injection of N-terminal Aβ fragment into the dorsal hippocampi of intact mice. The fragment-induced augmentation of fear conditioning was attenuated by coadministration of nicotinic antagonist. The activity of the N-terminal Aβ fragment appears to reside in a sequence surrounding a putative metal binding site at its the C-terminal region, YEVHHQ. This sequence is sufficient to both produce the aforementioned agonist-like action on nicotinic receptors in our rodent neuroblastoma cell line and augment fear conditioning in our mouse model. In addition to either the basic or aromatic properties, of the two histidine residues in the sequence it also appears that the aromatic properties of the initial tyrosine are required for the activity. These finding suggest that the N-terminal Aβ fragment may serve as a potent and effective endogenous neuromodulator.

Subjects/Keywords: N-terminal beta amyloid fragments

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APA (6^th Edition):

Lawrence, J. L. M. (2015). N-terminal beta amyloid fragments regulate nicotinic acetylcholine receptors. (Thesis). University of Hawaii – Manoa. Retrieved from http://hdl.handle.net/10125/101105

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):

Lawrence, James Le Marchant. “N-terminal beta amyloid fragments regulate nicotinic acetylcholine receptors.” 2015. Thesis, University of Hawaii – Manoa. Accessed March 08, 2021. http://hdl.handle.net/10125/101105.

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

MLA Handbook (7^th Edition):

Lawrence, James Le Marchant. “N-terminal beta amyloid fragments regulate nicotinic acetylcholine receptors.” 2015. Web. 08 Mar 2021.

Vancouver:

Lawrence JLM. N-terminal beta amyloid fragments regulate nicotinic acetylcholine receptors. [Internet] [Thesis]. University of Hawaii – Manoa; 2015. [cited 2021 Mar 08]. Available from: http://hdl.handle.net/10125/101105.

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

Council of Science Editors:

Lawrence JLM. N-terminal beta amyloid fragments regulate nicotinic acetylcholine receptors. [Thesis]. University of Hawaii – Manoa; 2015. Available from: http://hdl.handle.net/10125/101105

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

Louisiana State University

20. Bett, Cyrus Kipkurui. Amyloid Aggregation-Mitigating Peptides As Potential Alzheimer's Drugs.

Degree: PhD, Chemistry, 2009, Louisiana State University

URL: etd-09012009-140708 ; https://digitalcommons.lsu.edu/gradschool_dissertations/1865

► Neuronal cytotoxicity observed in Alzheimer¡¦s disease (AD) is linked to the aggregation of £]-amyloid peptide (A£]) into toxic forms. Increasing evidence points to oligomeric species… (more)

Subjects/Keywords: Amyloid aggregation

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APA (6^th Edition):

Bett, C. K. (2009). Amyloid Aggregation-Mitigating Peptides As Potential Alzheimer's Drugs. (Doctoral Dissertation). Louisiana State University. Retrieved from etd-09012009-140708 ; https://digitalcommons.lsu.edu/gradschool_dissertations/1865

Chicago Manual of Style (16^th Edition):

Bett, Cyrus Kipkurui. “Amyloid Aggregation-Mitigating Peptides As Potential Alzheimer's Drugs.” 2009. Doctoral Dissertation, Louisiana State University. Accessed March 08, 2021. etd-09012009-140708 ; https://digitalcommons.lsu.edu/gradschool_dissertations/1865.

MLA Handbook (7^th Edition):

Bett, Cyrus Kipkurui. “Amyloid Aggregation-Mitigating Peptides As Potential Alzheimer's Drugs.” 2009. Web. 08 Mar 2021.

Vancouver:

Bett CK. Amyloid Aggregation-Mitigating Peptides As Potential Alzheimer's Drugs. [Internet] [Doctoral dissertation]. Louisiana State University; 2009. [cited 2021 Mar 08]. Available from: etd-09012009-140708 ; https://digitalcommons.lsu.edu/gradschool_dissertations/1865.

Council of Science Editors:

Bett CK. Amyloid Aggregation-Mitigating Peptides As Potential Alzheimer's Drugs. [Doctoral Dissertation]. Louisiana State University; 2009. Available from: etd-09012009-140708 ; https://digitalcommons.lsu.edu/gradschool_dissertations/1865

University of South Carolina

21. Wang, Yiying. Stilbenes: Therapeutic Interventions Targeting Amyloid β Protein Aggregation In Alzheimer’s Disease.

Degree: PhD, Chemical Engineering, 2017, University of South Carolina

URL: https://scholarcommons.sc.edu/etd/4314

► Alzheimer’s disease (AD) is the most common form of dementia and accounts for 60-80 % of all dementia cases. In the United States, AD… (more)

▼ Alzheimer’s disease (AD) is the most common form of dementia and accounts for 60-80 % of all dementia cases. In the United States, AD is ranked as the 6th leading cause of death and it is the only one among the top 10 that cannot be prevented, treated or even slowed. All FDA approved drugs focus on attenuating the symptoms for a limited time by regulating neurotransmitters without any intervention with the underlying disease process. A major player in the initiation and development of this debilitating disorder is the misfolding and subsequent aggregating of amyloid-β (Aβ) peptide. This aggregation process converts non-toxic functional Aβ peptides into a spectrum of neurotoxic Aβ aggregated species, such as, oligomers, soluble aggregates and fibrils. These aggregated forms are believed to be the source of inflammation and oxidative stress that cause neuron death and the loss of synaptic functions. Therefore, small molecules that could intervene with the aggregation of Aβ peptides may present an effective AD therapeutic prevention and treatment. The work presented here examined the intervening effects of eight stilbenes, such as resveratrol and piceatannol, on multiple mechanistic steps of Aβ aggregation. Results identified trans-piceatannol and cis-piceatannol as the most potent compounds that could affect distinct aggregation pathways, specifically, modifying the conformation of Aβ aggregates, as well as, reducing soluble aggregate growth rate. The pronounced change in Aβ aggregate conformation might be related to a change in cytotoxicity. Their superior effects could be attributed to the presence of catechol moiety. The change in Aβ aggregate conformation induced by trans-piceatannol substantially reduced the Aβ aggregates binding to lipid bilayers, which plays a vital role in the induction of neurotoxicity. Other stilbenes, including resveratrol, also altered the morphology of Aβ aggregates but they exhibited only moderate interfering effects on Aβ aggregation pathways. Together, this study provides insight into the effective interventions of piceatannol on Aβ aggregation and proposes this natural compound as a novel promising small molecule for the prevention and treatment of AD. Advisors/Committee Members: Melissa A. Moss.

Subjects/Keywords: Chemical Engineering; Engineering; Alzheime; Amyloid

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APA (6^th Edition):

Wang, Y. (2017). Stilbenes: Therapeutic Interventions Targeting Amyloid β Protein Aggregation In Alzheimer’s Disease. (Doctoral Dissertation). University of South Carolina. Retrieved from https://scholarcommons.sc.edu/etd/4314

Chicago Manual of Style (16^th Edition):

Wang, Yiying. “Stilbenes: Therapeutic Interventions Targeting Amyloid β Protein Aggregation In Alzheimer’s Disease.” 2017. Doctoral Dissertation, University of South Carolina. Accessed March 08, 2021. https://scholarcommons.sc.edu/etd/4314.

MLA Handbook (7^th Edition):

Wang, Yiying. “Stilbenes: Therapeutic Interventions Targeting Amyloid β Protein Aggregation In Alzheimer’s Disease.” 2017. Web. 08 Mar 2021.

Vancouver:

Wang Y. Stilbenes: Therapeutic Interventions Targeting Amyloid β Protein Aggregation In Alzheimer’s Disease. [Internet] [Doctoral dissertation]. University of South Carolina; 2017. [cited 2021 Mar 08]. Available from: https://scholarcommons.sc.edu/etd/4314.

Council of Science Editors:

Wang Y. Stilbenes: Therapeutic Interventions Targeting Amyloid β Protein Aggregation In Alzheimer’s Disease. [Doctoral Dissertation]. University of South Carolina; 2017. Available from: https://scholarcommons.sc.edu/etd/4314

University of Canterbury

22. Domigan, Laura Joy. New nanomaterials: amyloid fibrils from waste proteins.

Degree: Doctor of Philosopy, Biochemistry, 2012, University of Canterbury

URL: http://dx.doi.org/10.26021/6175

► The current landscape of nanotechnology has focussed attention on materials that self-assemble. The search for such materials has unsurprisingly led to the biological world, where… (more)

▼ The current landscape of nanotechnology has focussed attention on materials that self-assemble. The search for such materials has unsurprisingly led to the biological world, where functional nanoscale biomolecular assemblies are in abundance. Amyloid fibrils are one such self-assembling biological structure, formed when native proteins misfold into insoluble fibrous quaternary structures. This research has explored the use of amyloid fibrils formed from waste proteins, namely crude crystallin proteins from fish eye lenses, as biological nanowires. The use of amyloid fibrils as nanowires was investigated by examining the ability to control their dimensions and arrangement, along with analysis of their properties, such as stability and conductivity. TEM and AFM studies on the model amyloid forming protein, bovine insulin, showed that a number of fibril length distributions can be achieved, by systematically altering fibril growth and storage conditions. Although the same set of conditions cannot be directly applied to crystallin fibrils, these fibrils can also be produced on a range of length scales. Amyloid fibrils can be manipulated and aligned in a controlled manner by dielectrophoresis; this tool could later be used to incorporate amyloid fibrils into a biosensing or bioelectronics device. Dielectrophoresis was also used to immobilise crystallin fibrils between electrode pairs, in order to investigate the conductivity of small numbers of fibrils. These experiments complemented work carried out on the conductivity of amyloid fibril networks, using fabricated interdigitated electrodes. In the unmodified state, amyloid fibrils formed from bovine insulin, fungal hydrophobins, and crude crystallins were all shown to have low conductivity, with current values in the range of 10⁻⁸–10⁻¹⁰ A recorded at bias voltages of 0–2 V. Amyloid fibrils were used as a template for the synthesis of conductive nanowires, by modification with the conducting polymers polyaniline and polypyrrole, increasing conductivity by one and four orders of magnitude respectively. The functionalisation of fibrils with glucose oxidase enabled the creation of a very simple glucose sensing device. This device, consisting of a gold electrode modified with the glucose oxidase functionalised fibrils, showed an electrochemical response in the presence of glucose and the mediator FcOH. Future work is necessary to optimise the use of amyloid fibrils in this way; however, this study confirms a role for amyloid fibrils from a low cost source in bionanotechnology.

Subjects/Keywords: Amyloid fibrils; crystallins; nanomaterial

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APA (6^th Edition):

Domigan, L. J. (2012). New nanomaterials: amyloid fibrils from waste proteins. (Doctoral Dissertation). University of Canterbury. Retrieved from http://dx.doi.org/10.26021/6175

Chicago Manual of Style (16^th Edition):

Domigan, Laura Joy. “New nanomaterials: amyloid fibrils from waste proteins.” 2012. Doctoral Dissertation, University of Canterbury. Accessed March 08, 2021. http://dx.doi.org/10.26021/6175.

MLA Handbook (7^th Edition):

Domigan, Laura Joy. “New nanomaterials: amyloid fibrils from waste proteins.” 2012. Web. 08 Mar 2021.

Vancouver:

Domigan LJ. New nanomaterials: amyloid fibrils from waste proteins. [Internet] [Doctoral dissertation]. University of Canterbury; 2012. [cited 2021 Mar 08]. Available from: http://dx.doi.org/10.26021/6175.

Council of Science Editors:

Domigan LJ. New nanomaterials: amyloid fibrils from waste proteins. [Doctoral Dissertation]. University of Canterbury; 2012. Available from: http://dx.doi.org/10.26021/6175

Georgia Tech

23. Chandramowlishwaran, Pavithra. Prion nucleation and propagation by mammalian amyloidogenic proteins in yeast.

Degree: PhD, Biology, 2018, Georgia Tech

URL: http://hdl.handle.net/1853/61159

► Cross-β fibrous protein polymers or “amyloids” are associated with a variety of human and animal diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s… (more)

▼ Cross-β fibrous protein polymers or “amyloids” are associated with a variety of human and animal diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) and are suspected to possess transmissible (prion) properties. However, the molecular mechanisms of amyloid formation and propagation are difficult to investigate in vivo due to complexity of the human organism. While evolutionarily distant from humans, yeast cells carry transmissible amyloids (yeast prions) that can be detected phenotypically. The objectives of the work presented in this dissertation were to understand the molecular mechanisms of initial prion nucleation and propagation by mammalian proteins in yeast. Our model employed chimeric constructs, containing the mammalian amyloidogenic proteins (or domains) fused to various fragments of the yeast prion protein Sup35. Phenotypic and biochemical detection assays, previously developed for the Sup35 prion, enabled us to detect prion nucleation and propagation by mammalian proteins. We have demonstrated that several non-Q/N rich, mammalian amyloidogenic proteins, nucleated a prion in yeast in the absence of pre-existing prions. Sequence alterations antagonizing or enhancing amyloidogenicity of human Aβ (associated with AD) and mouse PrP (associated with prion diseases) respectively antagonized or enhanced nucleation of a yeast prion by these proteins. Mutational dissection of Aβ identified sequences and chemicals that influence initial amyloid nucleation. We have also shown that Aβ and microtubule-associated binding protein tau that is also associated with AD, could propagate a prion state on their own or after transfection with in vitro generated amyloid seeds, in yeast. Aβ- and tau-based chimeric constructs formed distinct variants (“strains”) in the yeast cell. Our data show that prion properties of mammalian proteins detected in the yeast assays correspond with those found in mammals or in vitro, thus making yeast a powerful model for deciphering molecular foundations of amyloid/prion diseases. Advisors/Committee Members: Chernoff, Yury (advisor), Lobachev, Kirill (committee member), Lieberman, Raquel (committee member), Storici, Francesca (committee member), Conticello, Vincent (committee member).

Subjects/Keywords: Nucleation; Propagation; Amyloid; Yeast; Prion

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APA (6^th Edition):

Chandramowlishwaran, P. (2018). Prion nucleation and propagation by mammalian amyloidogenic proteins in yeast. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/61159

Chicago Manual of Style (16^th Edition):

Chandramowlishwaran, Pavithra. “Prion nucleation and propagation by mammalian amyloidogenic proteins in yeast.” 2018. Doctoral Dissertation, Georgia Tech. Accessed March 08, 2021. http://hdl.handle.net/1853/61159.

MLA Handbook (7^th Edition):

Chandramowlishwaran, Pavithra. “Prion nucleation and propagation by mammalian amyloidogenic proteins in yeast.” 2018. Web. 08 Mar 2021.

Vancouver:

Chandramowlishwaran P. Prion nucleation and propagation by mammalian amyloidogenic proteins in yeast. [Internet] [Doctoral dissertation]. Georgia Tech; 2018. [cited 2021 Mar 08]. Available from: http://hdl.handle.net/1853/61159.

Council of Science Editors:

Chandramowlishwaran P. Prion nucleation and propagation by mammalian amyloidogenic proteins in yeast. [Doctoral Dissertation]. Georgia Tech; 2018. Available from: http://hdl.handle.net/1853/61159

University of Manchester

24. Jackson, Joshua Daniel. Investigating Therapeutic Strategies in a Preclinical Model for Alzheimerâ€™s Disease.

Degree: 2017, University of Manchester

URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:310577

► Alzheimerâ€™s disease (AD) is a worldwide, incurable disease, and the most common form of dementia. Numbers of cases are rising, and since its discovery the… (more)

▼ Alzheimerâ€™s disease (AD) is a worldwide, incurable disease, and the most common form of dementia. Numbers of cases are rising, and since its discovery the only approved medications have treated only the symptoms, not the pathological cause. With the cost to society rising, the debilitating nature of the disease and the pressure put on the family members and support network of patients, disease modifying therapies are in dire need. Current models have proven an invaluable tool with which to study certain aspects of the disease and the genetics behind it, however the lack of clinically approved medications in the last 20 years suggests new models are needed. Based on the amyloid cascade hypothesis, this thesis initially characterises two models of Î²-Amyloid oligomer (AÎ²o) induced cognitive deficits. Both models are created by ICV injection of soluble AÎ²o into the brain of rat. The models differ only by the molecular weight of the AÎ²o 1-42, one, referred to as low molecular weight (LMW) AÎ²o, with stable dimers, trimers and tetramers, the other, referred to as high molecular weight (HMW) AÎ²o, consisting of assemblies ranging from ~50 to ~150 kDa. It was found that behavioural deficits were similar between the two, with a robust object recognition deficit, but no working memory deficit. Both models also showed a deficit in the synaptic marker PSD-95; however the LMW AÎ²o caused a deficit in the frontal cortex, whereas the HMW AÎ²o caused a hippocampal deficit. The role of the cellular prion protein (PrPC) was explored, by blocking its binding to AÎ²o with the antibody 6D11. Interestingly the two models showed different results. The HMW AÎ²o deficits were completely blocked by the 6D11 application, however the LMW AÎ²o deficits were only partially prevented. Finally, Fasudil, a vasodilator approved in parts of Asia, was used to inhibit Rho-kinase, showing a prevention of the cognitive deficits in the HMW AÎ²o model. The results of this thesis show the ICV administration of AÎ²o to be a useful model for investigating the effects of AÎ²o, provides a platform with which to study the differing effects of AÎ²o with different oligomeric assemblies, and a model to test therapeutic strategies with relevance to AD. Advisors/Committee Members: STRATFORD, IAN IJ, NEILL, JOANNA J, Harte, Michael, Stratford, Ian, Neill, Joanna.

Subjects/Keywords: Alzheimer; Disease Model; Amyloid

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APA (6^th Edition):

Jackson, J. D. (2017). Investigating Therapeutic Strategies in a Preclinical Model for Alzheimerâ€™s Disease. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:310577

Chicago Manual of Style (16^th Edition):

Jackson, Joshua Daniel. “Investigating Therapeutic Strategies in a Preclinical Model for Alzheimerâ€™s Disease.” 2017. Doctoral Dissertation, University of Manchester. Accessed March 08, 2021. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:310577.

MLA Handbook (7^th Edition):

Jackson, Joshua Daniel. “Investigating Therapeutic Strategies in a Preclinical Model for Alzheimerâ€™s Disease.” 2017. Web. 08 Mar 2021.

Vancouver:

Jackson JD. Investigating Therapeutic Strategies in a Preclinical Model for Alzheimerâ€™s Disease. [Internet] [Doctoral dissertation]. University of Manchester; 2017. [cited 2021 Mar 08]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:310577.

Council of Science Editors:

Jackson JD. Investigating Therapeutic Strategies in a Preclinical Model for Alzheimerâ€™s Disease. [Doctoral Dissertation]. University of Manchester; 2017. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:310577

Vanderbilt University

25. Barton, Shawn Michael. Innovations in Delivery of Theranostic Agents Across Biological Barriers for Applications in Alzheimer’s Disease.

Degree: PhD, Neuroscience, 2018, Vanderbilt University

URL: http://hdl.handle.net/1803/15303

► Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss, language deficits, and executive dysfunction. Currently, there are no disease-modifying therapeutics available and major… (more)

▼ Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss, language deficits, and executive dysfunction. Currently, there are no disease-modifying therapeutics available and major clinical trials have yielded no therapeutic benefits. Efforts to develop neurotherapeutics for AD and other neurologic disorders have been hindered by limited bioavailability due to the presence of the blood brain barrier (BBB). Previous attempts to target and clear amyloid beta (Aβ) plaques, a key pathologic mediator of AD, have had limited clinical success due to this biological barrier. To address this issue, we demonstrate in this work two distinct methods for improving delivery of theranostic agents to the brain. In one approach, using preclinical transgenic mouse models of AD, the BBB was breached in a condition amenable to acute inflammation, which allowed improved delivery of small and large materials to the brain parenchyma. Given the complexity of the biological and immunological events that emerge during inflammation, questions arise over the relative benefits and pernicious effects of this approach. Meanwhile, we demonstrated that aerosol administration also improves delivery to the brain without requiring BBB disruption, and thus may be more applicable to clinical translation. From a developmental biology perspective, the retina is part of the central nervous system, functioning as a window to the brain from where the neuronal activity in the retina is transferred to the higher order visual processing brain regions via the optic nerve. Our hypothesis is that if Aβ deposits are present in the retina, they could serve as a surrogate biomarker for those in the brain and thus offers an opportunity for noninvasive Aβ imaging. Toward that approach, we are developing a method of retinal plaque detection using fluorescent Aβ-binding molecules that could be visualized using noninvasive retinal imaging. Such a test could be used to clinically evaluate retinal pathology as a predictive biomarker for future development of AD. Advisors/Committee Members: John Gore (committee member), Douglas McMahon (committee member), Wellington Pham (committee member), Manus Donahue (Committee Chair).

Subjects/Keywords: Alzheimers; amyloid; retina; 5XFAD

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APA (6^th Edition):

Barton, S. M. (2018). Innovations in Delivery of Theranostic Agents Across Biological Barriers for Applications in Alzheimer’s Disease. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/15303

Chicago Manual of Style (16^th Edition):

Barton, Shawn Michael. “Innovations in Delivery of Theranostic Agents Across Biological Barriers for Applications in Alzheimer’s Disease.” 2018. Doctoral Dissertation, Vanderbilt University. Accessed March 08, 2021. http://hdl.handle.net/1803/15303.

MLA Handbook (7^th Edition):

Barton, Shawn Michael. “Innovations in Delivery of Theranostic Agents Across Biological Barriers for Applications in Alzheimer’s Disease.” 2018. Web. 08 Mar 2021.

Vancouver:

Barton SM. Innovations in Delivery of Theranostic Agents Across Biological Barriers for Applications in Alzheimer’s Disease. [Internet] [Doctoral dissertation]. Vanderbilt University; 2018. [cited 2021 Mar 08]. Available from: http://hdl.handle.net/1803/15303.

Council of Science Editors:

Barton SM. Innovations in Delivery of Theranostic Agents Across Biological Barriers for Applications in Alzheimer’s Disease. [Doctoral Dissertation]. Vanderbilt University; 2018. Available from: http://hdl.handle.net/1803/15303

University of Canterbury

26. Raynes, Jared Kenneth. Immobilising biomolecules on amyloid fibrils for biotechnology applications.

Degree: PhD, Biochemistry, 2012, University of Canterbury

URL: http://dx.doi.org/10.26021/9083

► Amyloid fibrils are an insoluble, highly ordered, fibrous protein structure, which have increasingly been recognised as having bionanotechnology applications. Their ability to selfassemble allows a… (more)

▼ Amyloid fibrils are an insoluble, highly ordered, fibrous protein structure, which have increasingly been recognised as having bionanotechnology applications. Their ability to selfassemble allows a bottom-up approach to material design. Their nanometre dimensions affords them a high surface-to-volume ratio and their proteinaceous building blocks from which they are assembled allow for decoration with biomolecules and chemicals through amino acid residues. Amyloid fibrils are therefore a potential nanoscaffold for immobilisation of biomolecules. Immobilisation offers a solution to the problems associated with the use of enzymes in in vitro applications, by increasing their stability, reusability, and in some cases, enhancing catalytic activity. Nanosupports offer a high surface-to-volume ratio compared to classical planar 2-D supports, potentially affording them dramatic increases in immobilisation capacity. To investigate the potential of amyloid fibrils as a novel nanoscaffold, organophosphate hydrolase (OPH), cytochrome P450BM3 (P450BM3), green fluorescent protein (GFP), tobacco etch virus protease (TEV), and glucose oxidase (GOD) were immobilised in solution to the model amyloid fibril forming protein, bovine insulin. Covalently immobilised OPH was found to have a ~300 % increase in relative thermostability at 40 and 50 °C. P450BM3 was not successfully immobilised in its active state, most likely due to unfolding of the enzyme on the amyloid fibril surface. Covalently immobilised GFP retained full fluorescence and acted as a fluorescent protein tag. TEV was shown to have a physical interaction with the nanoscaffold and retain activity. GOD was immobilised and retained activity. Although not all proteins retained activity, a range of different protein structures were successfully immobilised onto the insulin amyloid fibril nanoscaffold. Attachment to the crystallin amyloid fibril nanoscaffold remains a work in progress due to the complexities associated with post-translational modifications of these fibrils. Crystallin amyloid fibrils were assembled on a surface for the first time. Their surface assembled structure was found to resemble spherulites, not previously seen before with crystallin amyloid fibrils. Bovine insulin amyloid fibrils were assembled on the surface of glass beads to increase the available surface area for biomolecule immobilisation. The surface assembled bovine insulin nanoscaffold was first functionalised with GOD, demonstrating that the nanoscaffold provides more surface area for biomolecule immobilisation, although in this case the increase was limited due to high non-specific binding of GOD to the unmodified glass surface. GFP was successfully employed as a fluorescent protein tag to assess the degree of nanoscaffold coverage, confirming the nanoscaffold affords the glass bead a greater surface area. Moreover, a reusable immobilised TEV protease-bead system was developed that was able to sequentially cleave the poly-histidine tags of three different proteins. In conclusion,…

Subjects/Keywords: Amyloid; Immobilisation; Enzymes; Biotechnology; Nanotechnology

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

APA (6^th Edition):

Raynes, J. K. (2012). Immobilising biomolecules on amyloid fibrils for biotechnology applications. (Doctoral Dissertation). University of Canterbury. Retrieved from http://dx.doi.org/10.26021/9083

Chicago Manual of Style (16^th Edition):

Raynes, Jared Kenneth. “Immobilising biomolecules on amyloid fibrils for biotechnology applications.” 2012. Doctoral Dissertation, University of Canterbury. Accessed March 08, 2021. http://dx.doi.org/10.26021/9083.

MLA Handbook (7^th Edition):

Raynes, Jared Kenneth. “Immobilising biomolecules on amyloid fibrils for biotechnology applications.” 2012. Web. 08 Mar 2021.

Vancouver:

Raynes JK. Immobilising biomolecules on amyloid fibrils for biotechnology applications. [Internet] [Doctoral dissertation]. University of Canterbury; 2012. [cited 2021 Mar 08]. Available from: http://dx.doi.org/10.26021/9083.

Council of Science Editors:

Raynes JK. Immobilising biomolecules on amyloid fibrils for biotechnology applications. [Doctoral Dissertation]. University of Canterbury; 2012. Available from: http://dx.doi.org/10.26021/9083

University of Pennsylvania

27. Ferrie, John Joseph. Combining Computational And Experimental Approaches To Study Disordered And Aggregation Prone Proteins.

Degree: 2019, University of Pennsylvania

URL: https://repository.upenn.edu/edissertations/3586

► Over the past two decades disordered proteins have become more widely recognized, challenging the canonical structure-function paradigm associated with proteins. These highly dynamic proteins have… (more)

▼ Over the past two decades disordered proteins have become more widely recognized, challenging the canonical structure-function paradigm associated with proteins. These highly dynamic proteins have been identified across a wide range of species and play a variety of functional roles. Furthermore, the structural plasticity of these proteins gives way to their increased aggregation susceptibility, compared to canonical, well-folded proteins, placing disordered proteins at the center of many neurodegenerative diseases. Despite the increased recognition of the abundance and complexity of disordered proteins, their structural features and the mechanisms by which they transit between functional and pathological roles remains elusive. The efforts described herein focus on leveraging both experimental and computational approaches to study the structure and dynamics of these proteins. Fluorescence-based experiment have proven useful for studying these systems as the intrinsic heterogeneity of this class of proteins, which precludes the use of many traditional structural biochemistry techniques, can be accommodated. Therefore, initial efforts focused on developing new minimally perturbing fluorescence probes and coupling these probes with site-selective labeling strategies. Subsequent efforts focused on identifying methods which could predict where these probes would be tolerated to boost protein yield and avoid structural perturbation. These and other fluorescence probes were employed in Förster Resonance Energy Transfer (FRET) experiments, to study the conformational ensemble of α-synuclein, a disordered protein whose aggregation is implicated in Parkinson’s Disease pathogenesis. Experimental FRET data was paired with molecular modeling in PyRosetta to simulate the conformational ensembles of α-synuclein in the presence and absence of 2 M TMAO. The accuracy of the resultant ensembles was corroborated by comparison to other experimental data. Following this initial success using experimentally constrained simulations, attention was directed towards the development of algorithms capable of generating accurate structural representations of both disordered and ordered proteins de novo. Lastly, this work showcases the utility of a high-throughput in-silico screening approach in identifying a compound that binds selectively to α-synuclein fibrils with nanomolar affinity. Overall this work highlights several computational and experimental approaches which are broadly applicable to the study of disordered and aggregation prone proteins

Subjects/Keywords: amyloid; fluorescence; modeling; Chemistry

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

APA (6^th Edition):

Ferrie, J. J. (2019). Combining Computational And Experimental Approaches To Study Disordered And Aggregation Prone Proteins. (Thesis). University of Pennsylvania. Retrieved from https://repository.upenn.edu/edissertations/3586

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):

Ferrie, John Joseph. “Combining Computational And Experimental Approaches To Study Disordered And Aggregation Prone Proteins.” 2019. Thesis, University of Pennsylvania. Accessed March 08, 2021. https://repository.upenn.edu/edissertations/3586.

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

MLA Handbook (7^th Edition):

Ferrie, John Joseph. “Combining Computational And Experimental Approaches To Study Disordered And Aggregation Prone Proteins.” 2019. Web. 08 Mar 2021.

Vancouver:

Ferrie JJ. Combining Computational And Experimental Approaches To Study Disordered And Aggregation Prone Proteins. [Internet] [Thesis]. University of Pennsylvania; 2019. [cited 2021 Mar 08]. Available from: https://repository.upenn.edu/edissertations/3586.

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

Council of Science Editors:

Ferrie JJ. Combining Computational And Experimental Approaches To Study Disordered And Aggregation Prone Proteins. [Thesis]. University of Pennsylvania; 2019. Available from: https://repository.upenn.edu/edissertations/3586

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

NSYSU

28. 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

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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 March 08, 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. 08 Mar 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 Mar 08]. 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 the Western Cape

29. Teponnou, Gerard A. Kenfack. Tacrine, trolox and tryptoline as lead compounds for the design and synthesis of multi-target drugs for Alzheimer's disease therapy .

Degree: 2016, University of the Western Cape

URL: http://hdl.handle.net/11394/5344

► The cascade of neurotoxic events involved in the pathogenesis of Alzheimer's disease may explain the inefficacy of currently available treatment based on acetylcholinesterase inhibitors (AChEI… (more)

▼ The cascade of neurotoxic events involved in the pathogenesis of Alzheimer's disease may explain the inefficacy of currently available treatment based on acetylcholinesterase inhibitors (AChEI - donepezil, galantamine, rivastigmine) and N-methyl-D-aspartate (NMDA) antagonists (memantine). These drugs were designed based on the "one-moleculeone- target" paradigm and only address a single target. Conversely, the multi-target drug design strategy increasingly gains recognition. Based on the versatile biological activities of tacrine, trolox and β-carboline derivatives, the attention they have received as lead structures for the design of multifunctional drugs for the treatment of Alzheimer's disease, and the topology of the active site of AChE, we have designed tacrine-trolox and tacrine-tryptoline hybrids with various linker chain lengths. The aim with these hybrids was to provide additive or synergistic therapeutic effects that might help overcome the limitation of current anti Alzheimer's disease drugs. All synthesized compounds were designed from lead structures (tacrine, tryptoline and trolox) to obtain cholinesterase (ChE) multisite binders and multifunctional AD agents. The study was rationalized by docking all structures in the active site of TcAChE using Molecular Operating Environment (MOE) software before proceeding with the synthesis. ChE inhibition was assessed in a UV enzyme inhibition assay using Ellman's method. Antioxidant activities were assessed using the 2, 2-diphenyl-1-picrylhydrazyl (DPPH.) absorbance assay. The hybrids containing the trolox moiety (compounds 8a-e) showed moderate to high AChE inhibitory activity in the nano to micro molar range (IC₅₀: 17.37 - 2200 nM), BuChE inhibition was observed in the same range (IC₅₀: 3.16 – 128.82 nM), and free radical scavenging activities in micro molar range (IC50: 11.48 – 49.23 µM). These are comparable or slightly higher than their reference compounds donepezil (AChE IC₅₀ = 220 nM), tacrine (BuChE IC₅₀: 14.12 nM), and trolox (DPPH IC₅₀: 17.57 µM). The hybrids with longer linker chain lengths, 6 and 8 carbons (8d and 8e), showed better ChE inhibitory activity than the shorter ones, 2, 3, and 4 carbons (8a-c respectively). This correlates well with literature. Free radical scavenging activities, however, seems not to be significantly affected by varying linker chain lengths. The hybrid compound (14) containing the tryptoline moiety linked with a 7 carbon spacer displayed the best AChE and BuChE inhibitory activity (IC₅₀ = 17.37 and 3.16 nM) but poor free radical scavenging activity. Novel anti-Alzheimer's disease drugs with multi-target neuroprotective activities were thus obtained and hybrid molecules that exhibit good ChE inhibition (8d, 8e and 14) and anti-oxidant (8d and 8e) activity were identified as suitable candidates for further investigation. Advisors/Committee Members: Malan, Sarel F (advisor), Joubert, J (advisor).

Subjects/Keywords: Amyloid Beta; Cholinesterases; Alzheimer's disease; Multifunctional drugs; Amyloid beta-protein

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

APA (6^th Edition):

Teponnou, G. A. K. (2016). Tacrine, trolox and tryptoline as lead compounds for the design and synthesis of multi-target drugs for Alzheimer's disease therapy . (Thesis). University of the Western Cape. Retrieved from http://hdl.handle.net/11394/5344

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):

Teponnou, Gerard A Kenfack. “Tacrine, trolox and tryptoline as lead compounds for the design and synthesis of multi-target drugs for Alzheimer's disease therapy .” 2016. Thesis, University of the Western Cape. Accessed March 08, 2021. http://hdl.handle.net/11394/5344.

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

MLA Handbook (7^th Edition):

Teponnou, Gerard A Kenfack. “Tacrine, trolox and tryptoline as lead compounds for the design and synthesis of multi-target drugs for Alzheimer's disease therapy .” 2016. Web. 08 Mar 2021.

Vancouver:

Teponnou GAK. Tacrine, trolox and tryptoline as lead compounds for the design and synthesis of multi-target drugs for Alzheimer's disease therapy . [Internet] [Thesis]. University of the Western Cape; 2016. [cited 2021 Mar 08]. Available from: http://hdl.handle.net/11394/5344.

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

Council of Science Editors:

Teponnou GAK. Tacrine, trolox and tryptoline as lead compounds for the design and synthesis of multi-target drugs for Alzheimer's disease therapy . [Thesis]. University of the Western Cape; 2016. Available from: http://hdl.handle.net/11394/5344

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

Université Montpellier II

30. Ahmed, Abdullah. Dévelopement d'une méthode bio-informatique pour la prédiction des régions amyloidogéniques dans les protéines. : Development of bioinformatics method for prediction of amyloidogenic regions in proteins.

Degree: Docteur es, Biologie Santé, 2013, Université Montpellier II

URL: http://www.theses.fr/2013MON20051

►

La formation d'agrégats protéiques insolubles et fibreux, appelés fibrilles amyloïdes, est impliquée dans une large variété de maladies humaines. Parmi elles, figurent entre autres, le… (more)

▼

La formation d'agrégats protéiques insolubles et fibreux, appelés fibrilles amyloïdes, est impliquée dans une large variété de maladies humaines. Parmi elles, figurent entre autres, le diabète de type II, l'arthrite rhumatoïde et, notamment, les atteintes neurodégénératives débilitantes, telles que les maladies d'Alzheimer, de Parkinson ou encore de Huntington. Actuellement, il n'existe ni traitement, ni diagnostic précoce pour aucune de ces maladies.De nombreuses études ont montré que la capacité à former des fibrilles amyloïdes est une propriété inhérente à la chaîne polypeptidique. Ce constat a conduit au développement d'un certain nombre d'approches computationnelles permettant de prédire les propriétés amyloïdogéniques à partir de séquences d'amino-acides. Si ces méthodes s'avèrent très performantes vis à vis de courts peptides (~ 6 résidus), leur application à des séquences plus longues correspondant aux peptides et protéines en lien avec les maladies, engendre un nombre trop élevé de faux positifs. Le principal objectif de cette thèse consiste à développer une meilleure approche bioinformatique, capable de prédire les régions amyloïdogéniques à partir d'une séquence protéique. Récemment, l'utilisation de nouvelles techniques expérimentales a permis de mieux appréhender la structure des amyloïdes. Il est ainsi apparu que l'élément caractéristique de la majorité des fibrilles amyloïdes impliquées dans les maladies, était constitué d'une structure étagée (β-arcade), résultant de l'empilement de motifs « feuillet β – coude – feuillet b » appelés « β-arches ». Nous avons mis à profit cette particularité structurale pour créer une approche bioinformatique permettant de prédire les régions amyloïdogéniques d'une protéine à partir de l'information contenue dans sa séquence. Les résultats provenant de l'analyse des structures de type β-arcade, connues et modélisées, ont été compilés et traités à l'aide d'un algorithme écrit en langage Java, afin de créer le programme ArchCandy.L'application de ce programme à une sélection de séquences protéiques et peptidiques, connues pour leur lien avec les maladies, a permis de démontrer qu'il était en mesure de prédire correctement la majorité de ces séquences, de même que les séquences mutées impliquées dans les maladies familiales. Outre la prédiction de régions à haut potentiel amyloïde, ce programme suggère la conformation structurale adoptée par les fibrilles amyloïdes. Le séquençage de génomes entiers devenant toujours plus abordable, notre méthode offre une perspective de détermination individuelle des profils à risque, vis à vis de maladies neurodégénératives, liées à l'âge ou autres. Elle s'inscrit ainsi pleinement dans l'ère de la médecine personnalisée.

A broad range of human diseases are linked to the formation of insoluble, fibrous, protein aggregates called amyloid fibrils. They include, but are not limited to, type II diabetes, rheumatoid arthritis, and perhaps most importantly, debilitating neurodegenerative diseases such as Alzheimer's disease, Parkinson's…

Advisors/Committee Members: Kajava, Andrey (thesis director).

Subjects/Keywords: Bioinformatique; Amyloid; Maladie neurodégénérative; Bioinformatics; Amyloid; Neurodegenerative disease; Protein misfolding

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

APA (6^th Edition):

Ahmed, A. (2013). Dévelopement d'une méthode bio-informatique pour la prédiction des régions amyloidogéniques dans les protéines. : Development of bioinformatics method for prediction of amyloidogenic regions in proteins. (Doctoral Dissertation). Université Montpellier II. Retrieved from http://www.theses.fr/2013MON20051

Chicago Manual of Style (16^th Edition):

Ahmed, Abdullah. “Dévelopement d'une méthode bio-informatique pour la prédiction des régions amyloidogéniques dans les protéines. : Development of bioinformatics method for prediction of amyloidogenic regions in proteins.” 2013. Doctoral Dissertation, Université Montpellier II. Accessed March 08, 2021. http://www.theses.fr/2013MON20051.

MLA Handbook (7^th Edition):

Ahmed, Abdullah. “Dévelopement d'une méthode bio-informatique pour la prédiction des régions amyloidogéniques dans les protéines. : Development of bioinformatics method for prediction of amyloidogenic regions in proteins.” 2013. Web. 08 Mar 2021.

Vancouver:

Ahmed A. Dévelopement d'une méthode bio-informatique pour la prédiction des régions amyloidogéniques dans les protéines. : Development of bioinformatics method for prediction of amyloidogenic regions in proteins. [Internet] [Doctoral dissertation]. Université Montpellier II; 2013. [cited 2021 Mar 08]. Available from: http://www.theses.fr/2013MON20051.

Council of Science Editors:

Ahmed A. Dévelopement d'une méthode bio-informatique pour la prédiction des régions amyloidogéniques dans les protéines. : Development of bioinformatics method for prediction of amyloidogenic regions in proteins. [Doctoral Dissertation]. Université Montpellier II; 2013. Available from: http://www.theses.fr/2013MON20051

Open Access Theses and Dissertations