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However, the contribution of intracellular A\u03b2 or other cleavage products of its precursor protein (APP) to synaptic loss remains uncertain. In this study, we conducted a systematic examination of their cell-autonomous impact using a sparse expression system in rat hippocampal slice culture. Here, these proteins\/peptides were overexpressed in a single neuron, surrounded by thousands of untransfected neurons. Surprisingly, we found that APP induced dendritic spine loss only when co-expressed with BACE1. This effect was mediated by \u03b2-CTF, a \u03b2-cleavage product of APP, through an endosome-related pathway independent of A\u03b2. Neuronal expression of \u03b2-CTF in mouse brains resulted in defective synaptic transmission and cognitive impairments, even in the absence of amyloid plaques. These findings unveil a \u03b2-CTF-initiated mechanism driving synaptic toxicity irrespective of amyloid plaque formation and suggest a potential intervention by inhibiting the endosomal GTPase Rab5.<\/jats:p>","DOI":"10.7554\/elife.100968","type":"journal-article","created":{"date-parts":[[2024,9,9]],"date-time":"2024-09-09T16:25:55Z","timestamp":1725899155000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.100968","source":"Crossref","is-referenced-by-count":4,"title":["APP \u03b2-CTF triggers cell-autonomous synaptic toxicity independent of A\u03b2"],"prefix":"10.7554","volume":"13","author":[{"given":"Mengxun","family":"Luo","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01y3hvq34","id-type":"ROR","asserted-by":"publisher"}],"name":"Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences","place":["Shanghai, 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