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• W2100042032 abstract "The article by Jiang et al. (1) in this issue of PNAS goes a good way toward explaining early consequences of elevated expression of β-amyloid precursor protein (βAPP) and its β-secretase-cleaved carboxyl-terminal fragment (βCTF) in the endocytic dysfunction present early on in Alzheimer’s disease (AD) and Down’s syndrome (DS or trisomy 21). The authors pose a straightforward question: is duplication of the βAPP gene in DS sufficient to precipitate endocytic dysfunction? Using an elegantly simple approach in fibroblasts from individuals with trisomy 21 (3N), the authors show that either suppressing the expression of the extra βAPP gene by shRNA or decreasing the production of βCTF by inhibiting the βAPP β-secretase, BACE-1, reverses the dramatic pathologic changes in endocytic morphology (endosome enlargement) and function (accelerated uptake) noted in trisomy 21 or in βAPP overexpressing 2N fibroblasts. Their finding that overexpression of a mutated form of βAPP lacking the BACE-1 cleavage site in 2N fibroblasts did not produce the endocytic dysfunction showed conclusively that the mediating factor in the βAPP-related induction of endocytic dysfunction is βCTF. However, just to be sure that the endocytic anomalies necessitated only βCTF overexpression, they also showed that similar endocytic dysfunction is elicited when β amyloid (Aβ) production is reduced and βAPP and βCTF production is increased by γ-secretase inhibition in 2N cells. Findings such as these signify an important change, perhaps a sea change, in our understanding of the potential pathogenic role of overexpressing βAPP, relative to that of Aβ, at least in the arena of early endocytic dysfunction and its downstream consequences in AD and DS. Although Aβ continues to be the principal focus of investigations into both the causes and consequences of AD, these and other findings are beginning to highlight the fundamental importance of Aβ-independent pathogenic roles of βAPP and its various proteolytic products in AD." @default.
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• W2100042032 date "2010-01-26" @default.
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• W2100042032 title "Excess βCTF, not Aβ: The culprit in Alzheimer-related endocytic dysfunction" @default.
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• W2100042032 doi "https://doi.org/10.1073/pnas.0913922107" @default.
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