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

Zhongcong Xie12*, Yuanlin Dong12, Uta Maeda124, Weiming Xia3 and Rudolph E Tanzi1*

Author Affiliations

1 Department of Neurology, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129-2060, USA

2 Department of Anesthesia and Critical Care, Geriatric Anesthesia Research Unit, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129-2060, USA

3 Center for Neurological Diseases, Harvard Institute of Medicine and Harvard Medical School, Boston, MA 02115, USA

4 Graduate student, Department of Psychology, University of Southern California, Los Angeles, CA 90089, USA

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Translational Neurodegeneration 2012, 1:8  doi:10.1186/2047-9158-1-8

Published: 22 March 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.