{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:36:58Z","timestamp":1791920218258,"version":"4.3.4"},"reference-count":34,"publisher":"National Academy of Sciences","issue":"4","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,1,26]]},"abstract":"<jats:p>An additional copy of the \u03b2-amyloid precursor protein (APP) gene causes early-onset Alzheimer\u2019s disease (AD) in trisomy 21 (DS). Endosome dysfunction develops very early in DS and AD and has been implicated in the mechanism of neurodegeneration. Here, we show that morphological and functional endocytic abnormalities in fibroblasts from individuals with DS are reversed by lowering the expression of APP or \u03b2-APP-cleaving enzyme 1 (BACE-1) using short hairpin RNA constructs. By contrast, endosomal pathology can be induced in normal disomic (2N) fibroblasts by overexpressing APP or the C-terminal APP fragment generated by BACE-1 (\u03b2CTF), all of which elevate the levels of \u03b2CTFs. Expression of a mutant form of APP that cannot undergo \u03b2-cleavage had no effect on endosomes. Pharmacological inhibition of APP \u03b3-secretase, which markedly reduced A\u03b2 production but raised \u03b2CTF levels, also induced AD-like endosome dysfunction in 2N fibroblasts and worsened this pathology in DS fibroblasts. These findings strongly implicate APP and the \u03b2CTF of APP, and exclude A\u03b2 and the \u03b1CTF, as the cause of endocytic pathway dysfunction in DS and AD, underscoring the potential multifaceted value of BACE-1 inhibition in AD therapeutics.<\/jats:p>","DOI":"10.1073\/pnas.0908953107","type":"journal-article","created":{"date-parts":[[2009,12,28]],"date-time":"2009-12-28T21:10:18Z","timestamp":1262034618000},"page":"1630-1635","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":272,"title":["Alzheimer\u2019s-related endosome dysfunction in Down syndrome is A\u03b2-independent but requires APP and is reversed by BACE-1 inhibition"],"prefix":"10.1073","volume":"107","author":[{"given":"Ying","family":"Jiang","sequence":"first","affiliation":[{"name":"Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962;"},{"name":"Departments of 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