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 

作者机构：Department of NeurologyGenetics and Aging Research UnitMassGeneral Institute for Neurodegenerative DiseaseMassachusetts General Hospital and Harvard Medical SchoolCharlestownMA 02129-2060USA Department of Anesthesia and Critical CareGeriatric Anesthesia Research UnitMassachusetts General Hospital and Harvard Medical SchoolCharlestownMA 02129-2060USA Center for Neurological DiseasesHarvard Institute of Medicine and Harvard Medical SchoolBostonMA 02115USA Graduate studentDepartment of PsychologyUniversity of Southern CaliforniaLos AngelesCA 90089USA. 

出 版 物：《Translational Neurodegeneration》 (转化神经变性病（英文）)

年 卷 期：2012年第1卷第1期

页      面：45-54页

学科分类：0809[工学-电子科学与技术（可授工学、理学学位）] 08[工学] 

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.) 

主　　题：APP impaired attractive 

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 *** 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 *** we describe,for the first time,the effects of RNAi knock-down of Dab and Numb expression on APP processing and Ab *** 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 ***,RNAi knock-down of APP also reduced levels of Numb in H4-APP *** findings suggest that pharmacologically blocking interaction of APP with Dab and Numb may provide novel therapeutic strategies of *** 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,***,might be avoided.