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

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

doi:10.1038/s41586-023-06120-6

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

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Depp, Constanze
Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Sun, Ting
Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

/persons/resource/persons271994

Sasmita, Andrew O.
Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Spieth, Lena
Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Berghoff, Stefan A.
Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Nazarenko, Taisiia
Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Overhoff, Katharina
Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Steixner-Kumar, Agnes A.
Research Group of Clinical Neuroscience, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Subramanian, Swati
Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

/persons/resource/persons214271

Arinrad, Sahab
Research Group of Clinical Neuroscience, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

/persons/resource/persons182382

Ruhwedel, Torben
Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Möbius, Wiebke
Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

/persons/resource/persons182163

Göbbels, Sandra
Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

/persons/resource/persons182386

Saher, Gesine
Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Werner, Hauke B.
Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Krueger-Burg, Dilja
Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

/persons/resource/persons182138

Ehrenreich, Hannelore
Research Group of Clinical Neuroscience, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

/persons/resource/persons182427

Stassart, Ruth M.
Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Nave, Klaus-Armin
Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Citation

Depp, C., Sun, T., Sasmita, A. O., Spieth, L., Berghoff, S. A., Nazarenko, T., et al. (2023). Myelin dysfunction drives amyloid-β deposition in models of Alzheimer's disease. Nature, 618, 349-357. doi:10.1038/s41586-023-06120-6.

Cite as: https://hdl.handle.net/21.11116/0000-000D-3A17-9

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, the latter of which is associated with secondary neuroinflammation. As oligodendrocytes support axonal energy metabolism and neuronal health, 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.