Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease

2023 | journal article. A publication with affiliation to the University of Göttingen.

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​Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease​
Depp, C.; Sun, T.; Sasmita, A. O.; Spieth, L.; Berghoff, S. A.; Nazarenko, T. & Overhoff, K. et al.​ (2023) 
Nature618(7964) pp. 349​-357​.​ DOI: https://doi.org/10.1038/s41586-023-06120-6 

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Authors
Depp, Constanze; Sun, Ting; Sasmita, Andrew Octavian; Spieth, Lena; Berghoff, Stefan A.; Nazarenko, Taisiia; Overhoff, Katharina; Steixner-Kumar, Agnes A.; Subramanian, Swati; Arinrad, Sahab; Nave, Klaus-Armin
Abstract
Abstract The incidence of Alzheimer’s disease (AD), the leading cause of dementia, increases rapidly with age, but why age constitutes the main risk factor is still poorly understood. Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths 1 , the latter of which is associated with secondary neuroinflammation 2,3 . As oligodendrocytes support axonal energy metabolism and neuronal health 4–7 , we hypothesized that loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the central neuropathological hallmark of AD. Here we identify genetic pathways of myelin dysfunction and demyelinating injuries as potent drivers of amyloid deposition in mouse models of AD. Mechanistically, myelin dysfunction causes the accumulation of the Aβ-producing machinery within axonal swellings and increases the cleavage of cortical amyloid precursor protein. Suprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia despite an overall increase in their numbers. Bulk and single-cell transcriptomics of AD mouse models with myelin defects show that there is a concomitant induction of highly similar but distinct disease-associated microglia signatures specific to myelin damage and amyloid plaques, respectively. Despite successful induction, amyloid disease-associated microglia (DAM) that usually clear amyloid plaques are apparently distracted to nearby myelin damage. Our data suggest a working model whereby age-dependent structural defects of myelin promote Aβ plaque formation directly and indirectly and are therefore an upstream AD risk factor. Improving oligodendrocyte health and myelin integrity could be a promising target to delay development and slow progression of AD.
Issue Date
2023
Journal
Nature 
Project
TRR 274: Checkpoints of Central Nervous System Recovery 
TRR 274 | C01: Oligodendroglial NMDA receptors and NMDAR1 autoantibodies as determinants of axonal integrity in neuropsychiatric disease 
Working Group
RG Ehrenreich (Clinical Neuroscience) 
RG Nave (Neurogenetics) 
RG Simons (The Biology of Glia in Development and Disease) 
External URL
https://rdp.sfb274.de/literature/publications/134
ISSN
0028-0836
eISSN
1476-4687
Language
English

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