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The β-secretase enzyme BACE1 as a therapeutic target for Alzheimer's disease

DOI: 10.1186/alzrt82

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Abstract:

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 (Aβ) peptide plays a central role in AD pathogenesis. Consequently, therapeutic approaches to lower brain Aβ levels should be efficacious for the treatment or prevention of AD. Aβ is generated through the sequential endoproteolysis of APP by the β-secretase and γ-secretase enzymes (reviewed in [2]). β-secretase cuts first at the N-terminus of Aβ; γ-secretase cleaves only thereafter to make the C-terminus of Aβ. Then Aβ is secreted from neurons to form amyloid plaques in the AD brain. Inhibition of β-secretase should thus decrease production of Aβ, the pathogenic form of the peptide.Since the discovery of Aβ, the molecular identity of the β-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 β-secretase activity in cells and tissues had been extensively characterized. In 1999 five groups reported the molecular cloning of the β-secretase [3], variously naming the enzyme BACE [4], Asp2 [5,6], or memapsin 2 [7] (herein, β-secretase will be referred to as β-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 β-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

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