| 2 | RNAi-mediated knock-down of Dab and Numb attenuate Ab levels via g-secretase mediated APP processing显示文摘Amyloid-b-protein(Ab),the key component of senile plaques in Alzheimer’s disease(AD)brain,is produced from amyloid precursor protein(APP)by cleavage of b-secretase and then g-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 Ab 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 Ab levels in both cell lines by inhibiting g-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 g-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 gsecretase inhibition owing to impaired proteolysis of other g-secretase substrates,e.g.Notch,might be avoided. | Zhongcong Xie Yuanlin Dong Uta Maeda Weiming Xia Rudolph E Tanzi | 2012 | Translational Neurodegeneration2012，1，1： | 0 |
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