Abstract
Amyloid plaques are defining histopathologic lesions in the brains of Alzheimer's disease (AD) patients and are composed of the amyloid-beta peptide, which is widely considered to play a critical role in the pathogenesis of AD. The β-secretase, or β-site amyloid precursor protein cleaving enzyme 1 (BACE1; also called Asp2, memapsin 2), is the enzyme that initiates the generation of amyloid beta. Consequently, BACE1 is an attractive drug target for lowering cerebral levels of amyloid beta for the treatment or prevention of AD. Much has been learned about BACE1 since its discovery over 10 years ago. In the present article, we review BACE1 properties and characteristics, cell biology, in vivo validation, substrates, therapeutic potential, and inhibitor drug development. Studies relating to the physiological functions of BACE1 and the promise of BACE1 inhibition for AD will also be discussed. We conclude that therapeutic inhibition of BACE1 should be efficacious for AD, although careful titration of the drug dose may be necessary to limit mechanism-based side effects.
Highlights
Amyloid plaques are defining histopathologic lesions in the brains of Alzheimer’s disease (AD) patients and are composed of the amyloid-beta peptide, which is widely considered to play a critical role in the pathogenesis of AD
Discovery of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), the Alzheimer’s β-secretase Autosomal dominant mutations in the genes for amyloid precursor protein (APP) and the presenilins cause familial Alzheimer’s disease (AD), and these findings together with others suggest that the amyloid-beta (Aβ) peptide plays a central role in AD pathogenesis
There is very early evidence for the prospect of anti-BACE1 monoclonal antibodies for AD treatment
Summary
Amyloid plaques are defining histopathologic lesions in the brains of Alzheimer’s disease (AD) patients and are composed of the amyloid-beta peptide, which is widely considered to play a critical role in the pathogenesis of AD. BACE1 overexpression or BACE1 knockdown increases or decreases production of Aβ and β-secretase-cleaved APP fragments, respectively [4]. Increased targeting of BACE1 to the lipid raft was suggested to enhance β-secretase processing of APP [21,22].
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have