%0 Journal Article
%T The ¦Â-secretase enzyme BACE1 as a therapeutic target for Alzheimer's disease
%A Robert Vassar
%A Patty C Kandalepas
%J Alzheimer's Research & Therapy
%D 2011
%I BioMed Central
%R 10.1186/alzrt82
%X Autosomal dominant mutations in the genes for amyloid precursor protein (APP) and the presenilins (presenilin-1 and presenilin-2) cause familial Alzheimer's disease (AD) (reviewed in [1]), and these findings together with others suggest that the amyloid-beta (A¦Â) peptide plays a central role in AD pathogenesis. Consequently, therapeutic approaches to lower brain A¦Â levels should be efficacious for the treatment or prevention of AD. A¦Â is generated through the sequential endoproteolysis of APP by the ¦Â-secretase and ¦Ã-secretase enzymes (reviewed in [2]). ¦Â-secretase cuts first at the N-terminus of A¦Â; ¦Ã-secretase cleaves only thereafter to make the C-terminus of A¦Â. Then A¦Â is secreted from neurons to form amyloid plaques in the AD brain. Inhibition of ¦Â-secretase should thus decrease production of A¦Â, the pathogenic form of the peptide.Since the discovery of A¦Â, the molecular identity of the ¦Â-secretase has been intensely sought because of its prime status as a drug target for AD. Prior to the enzyme's discovery, the properties of ¦Â-secretase activity in cells and tissues had been extensively characterized. In 1999 five groups reported the molecular cloning of the ¦Â-secretase [3], variously naming the enzyme BACE [4], Asp2 [5,6], or memapsin 2 [7] (herein, ¦Â-secretase will be referred to as ¦Â-site amyloid precursor protein cleaving enzyme 1 (BACE1)). The groups used different isolation methods (expression cloning, protein purification, genomics), yet all identified the same enzyme and agreed it possessed all the characteristics of ¦Â-secretase.BACE1 is a type 1 transmembrane aspartic protease related to the pepsins and retroviral aspartic proteases [3-7]. BACE1 activity has a low optimum pH [4], and the enzyme is predominantly localized in acidic intracellular compartments (for example, endosomes, trans-Golgi) with its active site in the lumen of the vesicle [3-8]. The highest expression levels of BACE1 are found in neurons [3,4]. Importantly, BACE1 overexpression or
%U http://alzres.com/content/3/3/20