Ageing-associated myelin dysfunction drives amyloid deposition in mouse models of Alzheimer’s disease
| Autor: | Oliver Wirths, Lena Spieth, Gesine Saher, Maik Thalmann, Christian Haass, Ting Sun, Takashi Saito, Klaus-Armin Nave, Riki Kawaguchi, Hannelore Ehrenreich, Daniel H. Geschwind, Sandra Göbbels, Stefan A. Berghoff, Takaomi C. Saido, Swati Subramanian, Andrew Octavian Sasmita, Ruth M. Stassart, Dilja Krueger-Burg, Michael Willem, Constanze Depp, Wiebke Möbius, Silvia Zampar, Agnes A. Steixner-Kumar |
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| Rok vydání: | 2021 |
| Předmět: |
0303 health sciences
Microglia biology Chemistry medicine.disease Oligodendrocyte Cell biology 03 medical and health sciences Myelin 0302 clinical medicine medicine.anatomical_structure nervous system Ageing Forebrain medicine Amyloid precursor protein biology.protein Alzheimer's disease Beta (finance) 030217 neurology & neurosurgery 030304 developmental biology |
| Zdroj: | bioRxiv |
| Popis: | 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 affects oligodendrocytes1 and the structural integrity of myelin sheaths2, the latter associated with secondary neuroinflammation3. Since oligodendrocytes support axonal and neuronal health4–7, 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. Here, we show that in AD mouse models different genetically induced defects of myelin integrity or demyelinating injuries are indeed potent drivers of amyloid deposition in vivo, quantified by whole brain light sheet microscopy. 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 as revealed by bulk and single cell transcriptomics. These activated microglia, however, are primarily engaged with myelin, preventing the protective reactions of microglia to Aβ plaques. 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.g |
| Databáze: | OpenAIRE |
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