{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T13:04:41Z","timestamp":1768482281092,"version":"3.49.0"},"posted":{"date-parts":[[2019,4,23]]},"group-title":"Neuroscience","reference-count":101,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2019,4,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Aging increases the risk of Alzheimer\u2019s disease (AD). During normal aging synapses decline and \u03b2-Amyloid (A\u03b2) accumulates. An A\u03b2 defective clearance with aging is postulated as responsible for A\u03b2 accumulation, although a role for increased A\u03b2 production with aging can also lead to A\u03b2 accumulation. To test this hypothesis, we established a long-term culture of primary mouse neurons that mimics neuronal aging (lysosomal lipofuscin accumulation and synapse decline). Intracellular endogenous A\u03b242 accumulated in aged neurites due to increased amyloid-precursor protein (APP) processing. We show that APP processing is up-regulated by a specific age-dependent increase in APP endocytosis. Endocytosed APP accumulated in early endosomes that, in turn were found augmented in aged neurites. APP processing and early endosomes up-regulation was recapitulated in vivo. Finally, we found that inhibition of A\u03b2 production reduced the decline in synapses in aged neurons. We propose that potentiation of APP endocytosis by neuronal aging increases A\u03b2 production, which contributes to aging-dependent decline in synapses.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Summary<\/jats:title>\n                  <jats:p>How aging increases the risk of Alzheimer\u2019s disease is not clear. We show that normal neuronal aging increases the intracellular production of \u03b2-amyloid, due to an upregulation of the amyloid precursor protein endocytosis. Importantly, increased A\u03b2 production contributes to the aging-dependent synapse loss.<\/jats:p>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"616540v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/616540","type":"posted-content","created":{"date-parts":[[2019,4,23]],"date-time":"2019-04-23T20:04:10Z","timestamp":1556049850000},"source":"Crossref","is-referenced-by-count":4,"title":["Neuronal aging potentiates beta-amyloid generation via amyloid precursor protein 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