RNAi-Mediated Knock-Down of Dab and Numb Attenuate Aβ Levels via γ-Secretase Mediated APP Processing

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RNAi-Mediated Knock-Down of Dab and Numb Attenuate Aβ Levels via γ-Secretase Mediated APP Processing

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Title: RNAi-Mediated Knock-Down of Dab and Numb Attenuate Aβ Levels via γ-Secretase Mediated APP Processing
Author: Dong, Yuanlin; Maeda, Uta; Xia, Weiming; Xie, Zhongcong; Tanzi, Rudolph Emile

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Citation: Xie, Zhongcong, Yuanlin Dong, Uta Maeda, Weiming Xia, and Rudolph E. Tanzi. 2012. RNAi-mediated knock-down of Dab and Numb attenuate Aβ levels via γ-secretase mediated APP processing. Translational Neurodegeneration 1:8.
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Abstract: Amyloid-β-protein (Aβ), the key component of senile plaques in Alzheimer's disease (AD) brain, is produced from amyloid precursor protein (APP) by cleavage of β-secretase and then γ-secretase. APP adaptor proteins with phosphotyrosine-binding (PTB) domains, including Dab (gene: DAB) and Numb (gene: NUMB), can bind to and interact with the conserved YENPTY-motif in the APP C-terminus. Here we describe, for the first time, the effects of RNAi knock-down of Dab and Numb expression on APP processing and Aβ production. RNAi knock-down of Dab and Numb in H4 human neuroglioma cells stably transfected to express either FL-APP (H4-FL-APP cells) or APP-C99 (H4-APP-C99 cells) increased levels of APP-C-terminal fragments (APP-CTFs) and lowered Aβ levels in both cell lines by inhibiting γ-secretase cleavage of APP. Finally, RNAi knock-down of APP also reduced levels of Numb in H4-APP cells. These findings suggest that pharmacologically blocking interaction of APP with Dab and Numb may provide novel therapeutic strategies of AD. The notion of attenuating γ-secretase cleavage of APP via the APP adaptor proteins, Dab and Numb, is particularly attractive with regard to therapeutic potential, given that side effects of γ-secretase inhibition owing to impaired proteolysis of other γ-secretase substrates, e.g. Notch, might be avoided.
Published Version: doi:10.1186/2047-9158-1-8
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514095/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10579226
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