Proteostasis and lysosomal quality control deficits in Alzheimer’s disease neurons

Output Details

Preprint August 14, 2023

Ageing is the most prominent risk factor for Alzheimer’s disease (AD). However, the cellular mechanisms linking neuronal proteostasis decline to the characteristic aberrant protein deposits in the brains of patients with AD remain elusive. Here we develop transdifferentiated neurons (tNeurons) from human dermal fibroblasts as a neuronal model that retains ageing hallmarks and exhibits AD-linked vulnerabilities. Remarkably, AD tNeurons accumulate proteotoxic deposits, including phospho-tau and amyloid β, resembling those in APP mouse brains and the brains of patients with AD. Quantitative tNeuron proteomics identify ageing- and AD-linked deficits in proteostasis and organelle homeostasis, most notably in endosome– lysosomal components. Lysosomal deficits in aged tNeurons, including constitutive lysosomal damage and ESCRT-mediated lysosomal repair defects, are exacerbated in AD tNeurons and linked to inflammatory cytokine secretion and cell death. Providing support for the centrality of lysosomal deficits in AD, compounds ameliorating lysosomal function reduce amyloid β deposits and cytokine secretion. Thus, the tNeuron model system reveals impaired lysosomal homeostasis as an early event of ageing and AD.
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  • Original Research

Meet the Authors

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    Ching Chieh (Ian) Chou, PhD

    Key Personnel: Team Harper

    Stanford University

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    Ryan Vest

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    Miguel A. Prado

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    Joshua Wilson-Grady

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    Joao A. Paulo

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    Yohei Shibuya

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    Patricia Moran-Losada

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    Ting-Ting Lee

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    Jian Luo

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    Steven P. Gygi

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    Jeffrey W. Kelley

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    Daniel Finley

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    Marius Werning

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    Tony Wyss-Coray

  • Judith Frydman

    Co-PI (Core Leadership): Team Harper

    Stanford University