Up-regulation of APP endocytosis by neuronal aging drives amyloid dependent-synapse loss

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title = "Up-regulation of APP endocytosis by neuronal aging drives amyloid dependent-synapse loss",
abstract = "Neuronal aging increases the risk of late-onset Alzheimer's disease. During normal aging, synapses decline, and β-amyloid (Aβ) accumulates intraneuronally. However, little is known about the underlying cell biological mechanisms. We studied normal neuronal aging using normal aged brain and aged mouse primary neurons that accumulate lysosomal lipofuscin and show synapse loss. We identify the up-regulation of amyloid precursor protein (APP) endocytosis as a neuronal aging mechanism that potentiates APP processing and Aβ production in vitro and in vivo. The increased APP endocytosis may contribute to the observed early endosomes enlargement in the aged brain. Mechanistically, we show that clathrin-dependent APP endocytosis requires F-actin and that clathrin and endocytic F-actin increase with neuronal aging. Finally, Aβ production inhibition reverts synaptic decline in aged neurons while Aβ accumulation, promoted by endocytosis up-regulation in younger neurons, recapitulates aging-related synapse decline. Overall, we identify APP endocytosis up-regulation as a potential mechanism of neuronal aging and, thus, a novel target to prevent late-onset Alzheimer's disease.",
author = "Tatiana Burrinha and Isak Martinsson and Ricardo Gomes and Terrasso, {Ana Paula} and Gouras, {Gunnar K} and Almeida, {Cl{\'a}udia Guimas}",
note = "{\textcopyright} 2021. Published by The Company of Biologists Ltd.",
year = "2021",
month = may,
day = "1",
doi = "10.1242/jcs.255752",
language = "English",
volume = "134",
journal = "The Quarterly journal of microscopical science",
issn = "0021-9533",
publisher = "The Company of Biologists Ltd",
number = "9",