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- W1946603937 abstract "β-Amyloid precursor protein (APP) and its cleaved products are strongly implicated in Alzheimer’s disease (AD). Endosomes are highly active APP processing sites, and endosome anomalies associated with upregulated expression of early endosomal regulator, rab5, are the earliest known disease-specific neuronal response in AD. Here, we show that the rab5 effector APPL1 (adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif) mediates rab5 overactivation in Down syndrome (DS) and AD, which is caused by elevated levels of the β-cleaved carboxy-terminal fragment of APP (βCTF). βCTF recruits APPL1 to rab5 endosomes, where it stabilizes active GTP-rab5, leading to pathologically accelerated endocytosis, endosome swelling and selectively impaired axonal transport of rab5 endosomes. In DS fibroblasts, APPL1 knockdown corrects these endosomal anomalies. βCTF levels are also elevated in AD brain, which is accompanied by abnormally high recruitment of APPL1 to rab5 endosomes as seen in DS fibroblasts. These studies indicate that persistent rab5 overactivation through βCTF–APPL1 interactions constitutes a novel APP-dependent pathogenic pathway in AD." @default.
- W1946603937 created "2016-06-24" @default.
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- W1946603937 creator A5085954451 @default.
- W1946603937 date "2015-07-21" @default.
- W1946603937 modified "2023-10-18" @default.
- W1946603937 title "Evidence that the rab5 effector APPL1 mediates APP-βCTF-induced dysfunction of endosomes in Down syndrome and Alzheimer’s disease" @default.
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- W1946603937 doi "https://doi.org/10.1038/mp.2015.97" @default.
- W1946603937 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4721948" @default.
- W1946603937 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26194181" @default.
- W1946603937 hasPublicationYear "2015" @default.
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