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Universität Tübingen

1. Degenhardt, Karoline. Modulation of cerebral β-amyloidosis by myeloid cells .

Degree: 2018, Universität Tübingen

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder and the most common form of dementia. Thereby, the abnormal deposition of the amyloid-β (Aβ) peptide into plaques is considered to be the primary neuropathological insult in AD. For a small proportion of all AD cases it is well known that rare genetic mutations are causative for very early Aβ deposition (familial Alzheimer’s disease). However, the vast majority of all AD cases manifest at later ages (late-onset Alzheimer’s disease (LOAD)) and are most likely caused by an interplay of multiple genetic variants and the environment. During the last ten years, genome-wide association studies revealed several risk loci that increase the susceptibility for LOAD, and interestingly, many of these genetic variants were found to be associated with innate immune functions of which the resident tissue macrophages of the brain – the microglia – are prime regulators. In general, the innate immune response mediated by the resident tissue macrophages is considered protective as it induces the production of inflammatory modulators and enables phagocytosis and killing of pathogens to prevent further tissue damage. However in the AD brain, the progressive accumulation of Aβ deposits leads to a chronic exposure of microglia to Aβ aggregates and induces an excessive neuro-inflammatory response that is thought to promote disease progression. Interestingly, microglia display a highly plastic phenotype and studies from peripheral tissue macrophages reported that a variety of environmental stimuli can determine but also reprogram their functional phenotype. To this end, this thesis summarizes three different approaches, which aimed to understand but also modulate the myeloid cell immune function during AD with regard to their effects on the pathology of cerebral β-amyloidosis. To begin with, we examined whether peripheral monocytes, which were previously shown to adopt a microglia-like phenotype in the healthy brain, can replace dysfunctional microglia in brains of two different mouse models of cerebral β-amyloidosis and may then restrict Aβ accumulation. For this purpose, we depleted microglia in APPPS1 and APP23 transgenic (tg) mice that expressed the herpes simplex virus thymidine kinase (HSVTK) under the myeloid-cell specific CD11b promoter; the application of the thymidine kinase substrate ganciclovir (GCV), which is converted into a cytotoxic product, then induced microglial death. After a two-week ganciclovir treatment, application was discontinued from two weeks up to six months to allow the peripheral monocytes to repopulate the brain. Interestingly, during the first weeks of repopulation the number of infiltrated monocytes were twice the number of resident microglia in control mice, but the engrafted monocytes failed to cluster around Aβ plaques. Consequently, we did not observe alterations in plaque pathology. Also, a pro-longed incubation for up to six months did not change Aβ load. However, long-term monocyte engraftment for… Advisors/Committee Members: Neher, Jonas (Dr.) (advisor).

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

APA (6th Edition):

Degenhardt, K. (2018). Modulation of cerebral β-amyloidosis by myeloid cells . (Thesis). Universität Tübingen. Retrieved from http://hdl.handle.net/10900/84349

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

Chicago Manual of Style (16th Edition):

Degenhardt, Karoline. “Modulation of cerebral β-amyloidosis by myeloid cells .” 2018. Thesis, Universität Tübingen. Accessed November 16, 2018. http://hdl.handle.net/10900/84349.

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

MLA Handbook (7th Edition):

Degenhardt, Karoline. “Modulation of cerebral β-amyloidosis by myeloid cells .” 2018. Web. 16 Nov 2018.

Vancouver:

Degenhardt K. Modulation of cerebral β-amyloidosis by myeloid cells . [Internet] [Thesis]. Universität Tübingen; 2018. [cited 2018 Nov 16]. Available from: http://hdl.handle.net/10900/84349.

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

Council of Science Editors:

Degenhardt K. Modulation of cerebral β-amyloidosis by myeloid cells . [Thesis]. Universität Tübingen; 2018. Available from: http://hdl.handle.net/10900/84349

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

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