%0 Journal Article
%T RNAi-mediated knock-down of Dab and Numb attenuate A¦Â levels via ¦Ã-secretase mediated APP processing
%A Zhongcong Xie
%A Yuanlin Dong
%A Uta Maeda
%A Weiming Xia
%A Rudolph E Tanzi
%J Translational Neurodegeneration
%D 2012
%I BioMed Central
%R 10.1186/2047-9158-1-8
%X Amyloid-¦Â-protein (A¦Â), the key component of senile plaques in Alzheimer's disease (AD) neuropathology, was first isolated from meningovascular amyloid deposits in AD and Down's syndrome [1,2], and has also been reported to be the subunit of the plaque amyloid [2-4]. The current amyloid hypothesis of AD states that the imbalance between A¦Â generation and A¦Â clearance is the basis of AD neuropathogenesis. A¦Â is generated from amyloid precursor protein (APP). Specifically, APP is first hydrolyzed by ¦Â-secretase to generate a 99-residue membrane-associated C-terminus fragment (APP-C99) [5-8]. APP-C99 is further cleaved to release a ~4-kDa peptide, A¦Â, and the amyloid precursor protein intracellular domain (AICD). This cleavage is achieved by an unusual form of proteolysis in which the protein is cleaved within the transmembrane domain (at residue +40 or +42) by ¦Ã-secretase [9-11]. ¦Á-secretase cleaves the majority of APP in the middle of the A¦Â region of APP. This cleavage will preclude A¦Â generation, lead to the release of a large ectodomain (¦Á-APPs), and leave behind a carboxy-terminus fragment of 83 amino acids (APP-C83) in the membrane. ¦Ã-Secretase cleaves APP-C83 to produce p3, an amino-terminally truncated form of A¦Â [12,13], [see review in [14]].The cleavage of the APP cytoplasmic tail by ¦Ã-secretase generates AICD, which contains the strongly conserved YENPTY-motif. The YENPTY-sequence is a consensus motif for the binding of adaptor proteins that possess a phosphotyrosine-binding domain (PTB) present in several APP adaptor proteins, such as X11, Fe65, ShcC, Numb, Dab and JIP families [see review in [15]]. We have previously reported that RNAi knock-down of X11¦Á, ShcC and Fe65 in H4 human neuroglioma cells lower A¦Â levels [16,17].Dab (encoded by gene DAB), the PTB-containing APP adaptor protein, can bind to and interact with the YENPTY-motif of APP [18,19]. Dab has been reported to function as an adaptor molecule in signal transduction process [20,21]. Numb (enco
%U http://www.translationalneurodegeneration.com/content/1/1/8