The contribution of oligodendrocytes to amyloid and tau pathologies in mouse models of Alzheimer’s disease
Dissertation
Datum der mündl. Prüfung:2023-12-14
Erschienen:2024-03-18
Betreuer:Prof. Dr. Klaus-Armin Nave
Gutachter:Prof. Dr. Thomas A. Bayer
Gutachter:Prof. Dr. Nils Brose
Dateien
Name:Sasmita_Thesis_Complete.pdf
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Description:Thesis
Diese Datei ist bis 13.12.2024 gesperrt.
Zusammenfassung
Englisch
Oligodendrocytes (OLs) are the myelinating glia of the CNS and are capable of metabolically supporting long axonal projections by providing local fuel production. OL and myelin health, however, start degrading around the second half of human life, which coincides with the predicted age at which Alzheimer’s disease (AD), a debilitating neurodegenerative disease, may begin to develop. Although AD is often considered a disease of the gray matter, or neurons to be exact, recent evidence has indicated the involvement of glial cells in its pathophysiology. Earlier work has shown that dysfunctional myelin is a risk factor for amyloid-β (Aβ) plaque burden, one of the hallmarks of AD. Thus, the general aim of this thesis is to expand our current understanding of the role of OL and myelin in the context of AD. In Chapter I, we investigated whether OLs, alongside excitatory neurons (ExNs), can generate Aβ in vivo. We first generated genetically modified mouse models of amyloidosis with cell-type specific ablation of β-secretase 1 (BACE1), the key enzyme in Aβ production. By combining quantitative light-sheet microscopy (LSM), 2D imaging, in vitro cultures, and a sensitive electrochemiluminescence assay, we report novel data showing that OLs contribute to Aβ plaque burden in vivo, especially in white matter regions where OLs predominate. ExNs, however, remain the primary contributor to Aβ production. Interestingly, genetic deletion of BACE1 in cortical and hippocampal ExNs resulted in major reductions in subcortical Aβ plaque burden. This suggests that Aβ processing can occur in white matter fibers originating from the forebrain and projecting into subcortical structures, where Aβ would then be released. By analyzing several mouse models generated for the current chapter, we propose that Aβ plaque deposition requires reaching a threshold Aβ concentration, and without the ExN Aβ contribution, Aβ concentration is initially insufficient to induce major plaque seeding. Together, findings from this chapter potentially advance our knowledge on Aβ plaque seeding and growth kinetics, and may further allow us to consider OLs as a viable target for anti-amyloid therapies such as BACE1 inhibitors. The objective of Chapter II was to expand on our previous study linking dysfunctional myelin and amyloid pathology by turning our focus to tau pathology. Although Aβ pathology precedes that of tau, tau pathology is still the known executioner of neuronal cell death in AD. We performed 2D imaging and a battery of behavioral tests on a mouse model of tauopathy, inducing acute and genetic dysmyelination in separate cohorts. We discovered that myelin damage heightened tau pathology in both experimental cases, with a stronger effect seen due to genetic dysmyelination. Worsening tau pathology also correlated with behavioral outcomes: Mice with myelin damage were much slower than control animal, experienced additive motor impairments alongside evident anxiety reduction and defects in cognitive processing. In sum, we preliminarily suggest that dysfunctional myelin leads to impairments that would worsen tau pathology in vivo. Finally, in Chapter III, we report a potential cause of the large discrepancies often seen in genetically modified mouse models of AD. By utilizing quantitative LSM on labeled hemibrains of 5xFAD mice, we observed that the transgenic inheritance pattern modulated amyloid plaque load after age- and sex-matching. Mice that inherited their transgenes from a paternal source developed significantly greater plaque burden than their maternal inheritance counterparts. This previously unreported effect is unlikely the result of maternal immune priming and instead, is likely due to epigenetic modulation on the transgene itself. Our findings could thus support the conduct of more reproducible experiments in the field of transgenic animal research. In conclusion, the work performed in this thesis indicates that OLs serve more contributory roles in AD than previously thought, in terms of both amyloid and tau pathologies. Our findings could expand on OLs and myelin as the missing link in the current knowledge on Aβ production and tau accumulation, potentially opening up new avenues for research on AD pathophysiology or the development of novel strategies to address AD pathogenesis.
Keywords: Alzheimer's disease; myelin; oligodendrocytes; neurodegeneration; amyloid-beta; plaque deposition