RNAi-mediated knock-down of Dab and Numb attenuate Ab levels via g-secretase mediated APP processing  

作　　者：Zhongcong Xie Yuanlin Dong Uta Maeda Weiming Xia Rudolph E Tanzi 

机构地区：[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.

出　　处：《Translational Neurodegeneration》2012年第1期45-54,共10页转化神经变性病（英文）

基　　金：This research was supported by K08NS048140,R21AG029856,R21AG038994 and R01 GM088801(National Institutes of Health),USA,Jahnigen Career Development Award(American Geriatrics Society),USA;Investigator Initiated Research Grant(Alzheimer’s Association),Cure Alzheimer’s Fund,USA(to Z.X.);MH 60009(National Institute of Mental Health),USA,Cure Alzheimer’s Fund(to R.T.).

摘　　要：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.

关 键 词：APP IMPAIRED ATTRACTIVE 

分 类 号：TN9[电子电信—信息与通信工程]