bioRxiv2021
The prevalence of Alzheimers 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-{beta} (A{beta}) 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 A{beta} 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 A{beta} 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