Oligodendrocytes and neurons contribute to amyloid-β deposition in Alzheimer’s 
disease

Sasmita, Andrew O.; Depp, Constanze; Nazarenko, Taisiia; Sun, Ting; Siems, Sophie B.; Yu, Xuan; Böhler, Carolin; Ong, Erinne Cherisse; Bues, Bastian; Evangelista, Lisa; Morgado, Barbara; Wu, Zoe; Ruhwedel, Torben; Subramanian, Swati; Börensen, Friederike; Overhoff, Katharina; Spieth, Lena; Berghoff, Stefan A.; Sadleir, Katherine Rose; Vassar, Robert; Eggert, Simone; Goebbels, Sandra; Saito, Takashi; Saido, Takaomi; Möbius, Wiebke; Castelo-Branco, Gonçalo; Klafki, Hans-Wolfgang; Wirths, Oliver; Wiltfang, Jens; Jäkel, Sarah; Yan, Riqiang; Nave, Klaus-Armin

doi:10.1101/2023.12.11.570514

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Oligodendrocytes and neurons contribute to amyloid-β deposition in Alzheimer’s disease

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

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Siems, Sophie B.
Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

Yu, Xuan
Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

/persons/resource/persons182091

Böhler, Carolin
Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

Ong, Erinne Cherisse
Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

Wu, Zoe
Department of Neurogenetics, 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;

/persons/resource/persons289897

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

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

/persons/resource/persons202532

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

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Eggert, Simone
Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

/persons/resource/persons182163

Goebbels, Sandra
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;

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

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Citation

Sasmita, A. O., Depp, C., Nazarenko, T., Sun, T., Siems, S. B., Yu, X., et al. (2023). Oligodendrocytes and neurons contribute to amyloid-β deposition in Alzheimer’s disease. bioRxiv. doi:10.1101/2023.12.11.570514.

Cite as: https://hdl.handle.net/21.11116/0000-000E-3B96-7

Abstract

In Alzheimer’s disease (AD), amyloid-β (Aβ) is thought to be of neuronal origin. However, in single-cell RNAseq datasets from mouse and human, we found transcripts of amyloid precursor protein (APP) and the amyloidogenic-processing machinery equally abundant in oligodendrocytes (OLs). By cell-type-specific deletion of Bace1 in a humanized knock-in AD model, APPNLGF, we demonstrate that almost a third of cortical Aβ deposited in plaques is derived from OLs. However, excitatory projection neurons must provide a threshold level of Aβ production for plaque deposition to occur and for oligodendroglial Aβ to co-aggregate. Indeed, very few plaques are deposited in the absence of neuronally-derived Aβ, although soluble Aβ species are readily detected, especially in subcortical white matter. Our data identify OLs as a source of Aβ in vivo and further underscore a non-linear relationship between cellular Aβ production and resulting plaque formation. Ultimately, our observations are relevant for therapeutic strategies aimed at disease prevention in AD.