In:
Alzheimer's & Dementia, Wiley, Vol. 18, No. S4 ( 2022-12)
Kurzfassung:
The prevalence of Alzheimer’s disease (AD), the leading cause of dementia, shows a strict age‐dependency, but why ageing constitutes the main risk factor for this disease is still poorly understood. Brain ageing markedly affects oligodendrocytes and the structural integrity of myelin sheaths which is associated with secondary gliosis. Since oligodendrocytes support axonal and neuronal health, we hypothesised that ageing‐associated loss of myelin integrity could be an upstream risk factor for neuronal amyloid‐β (Aβ) deposition, the primary neuropathological hallmark of AD. Method We used AD mouse models and combined them with genetic myelin dysfunction models (CNP −/− , PLP −/y, Emx‐Cre MBP fl/fl forebrain shiverer) as well as mouse models of acute demyelination (Cuprizone, EAE) and investigated the effect of myelin defects on amyloid deposition using in toto quantitative light sheet microscopy. Bulk and single cell transcriptomics, immunohistochemistry and biochemical approaches were used to investigate the potential mechanism of action. Result We identified myelin defects as potent drivers of amyloid deposition in vivo . Conversely, the lack of myelin in the forebrain provides protection against plaque deposition. Mechanistically, we find that myelin dysfunction causes the accumulation of the Aβ producing machinery within axonal swellings and increases cortical amyloid precursor protein (APP) cleavage. Surprisingly, AD mice with dysfunctional myelin lack plaque‐corralling microglia but show a disease‐associated microglia (DAM)‐like signature. These activated microglia, however, are primarily engaged with myelin, preventing the protective reactions of microglia to Aβ plaques. Conclusion Our data suggest a working model, in which age‐dependent structural defects of myelin promote plaque formation, directly and indirectly, and are thus an upstream AD risk factor. Improving oligodendrocyte health and myelin integrity could be a promising target to delay AD.
Materialart:
Online-Ressource
ISSN:
1552-5260
,
1552-5279
Sprache:
Englisch
Verlag:
Wiley
Publikationsdatum:
2022
ZDB Id:
2201940-6
