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Cell type-specific functions of Alzheimer's disease endocytic risk genes

Maninger, Johanna-Katharina, Nowak, Karolina, Goberdhan, Srilakshmi, O'Donoghue, Rachel and Connor-Robson, Natalie ORCID: 2024. Cell type-specific functions of Alzheimer's disease endocytic risk genes. Philosophical Transactions of the Royal Society B: Biological Sciences 379 (1899) , 20220378. 10.1098/rstb.2022.0378

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Endocytosis is a key cellular pathway required for the internalization of cellular nutrients, lipids and receptor-bound cargoes. It is also critical for the recycling of cellular components, cellular trafficking and membrane dynamics. The endocytic pathway has been consistently implicated in Alzheimer's disease (AD) through repeated genome-wide association studies and the existence of rare coding mutations in endocytic genes. BIN1 and PICALM are two of the most significant late-onset AD risk genes after APOE and are both key to clathrin-mediated endocytic biology. Pathological studies also demonstrate that endocytic dysfunction is an early characteristic of late-onset AD, being seen in the prodromal phase of the disease. Different cell types of the brain have specific requirements of the endocytic pathway. Neurons require efficient recycling of synaptic vesicles and microglia use the specialized form of endocytosis—phagocytosis—for their normal function. Therefore, disease-associated changes in endocytic genes will have varied impacts across different cell types, which remains to be fully explored. Given the genetic and pathological evidence for endocytic dysfunction in AD, understanding how such changes and the related cell type-specific vulnerabilities impact normal cellular function and contribute to disease is vital and could present novel therapeutic opportunities. This article is part of a discussion meeting issue ‘Understanding the endo-lysosomal network in neurodegeneration’.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Additional Information: License information from Publisher: LICENSE 1: URL:, Type: open-access
Publisher: The Royal Society
ISSN: 0962-8436
Date of First Compliant Deposit: 19 February 2024
Date of Acceptance: 12 September 2023
Last Modified: 19 Feb 2024 10:30

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