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Open Access 01-12-2012 | Research

RNAi-mediated knock-down of Dab and Numb attenuate Aβ levels via γ-secretase mediated APP processing

Authors: Zhongcong Xie, Yuanlin Dong, Uta Maeda, Weiming Xia, Rudolph E Tanzi

Published in: Translational Neurodegeneration | Issue 1/2012

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.

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Title: RNAi-mediated knock-down of Dab and Numb attenuate Aβ levels via γ-secretase mediated APP processing
Authors: Zhongcong Xie
Yuanlin Dong
Uta Maeda
Weiming Xia
Rudolph E Tanzi
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: Translational Neurodegeneration / Issue 1/2012
Electronic ISSN: 2047-9158
DOI: https://doi.org/10.1186/2047-9158-1-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

RNAi-mediated knock-down of Dab and Numb attenuate Aβ levels via γ-secretase mediated APP processing

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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