The incidence of Alzheimer's disease (AD) increases rapidly with age. Brain aging affects oligodendrocytes and myelin sheaths, which is associated with neuroinflammation. The authors hypothesized that loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition. They found that genetic pathways of myelin dysfunction drive amyloid deposition in mouse models of AD. Myelin dysfunction causes Aβ-producing machinery accumulation and increased amyloid precursor protein cleavage. Surprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia. Transcriptomics shows distinct microglia signatures specific to myelin damage and amyloid plaques. Amyloid disease-associated microglia (DAM) are distracted by myelin damage. Age-dependent myelin defects promote Aβ plaque formation, suggesting improving oligodendrocyte health could delay AD.

Constanze Depp, Ting Sun, Andrew Octavian Sasmita, Lena Spieth, Stefan A. Berghoff, Taisiia Nazarenko, Katharina Overhoff, Agnes A. Steixner-Kumar, Swati Subramanian, Sahab Arinrad, Torben Ruhwedel, Wiebke Möbius, Sandra Göbbels, Gesine Saher, Hauke B. Werner, Alkmini Damkou, Silvia Zampar, Oliver Wirths, Maik Thalmann, Mikael Simons, Takashi Saito, Takaomi Saido, Dilja Krueger-Burg, Riki Kawaguchi, Michael Willem, Christian Haass, Daniel Geschwind, Hannelore Ehrenreich, Ruth Stassart, Klaus-Armin Nave