The β-secretase enzyme BACE1 as a therapeutic target for Alzheimers disease 英文参考文献.docVIP

Vassar and Kandalepas Alzheimer’s Research Therapy 2011,3:20 /content/3/3/20 RE VIE W The β-secretase enzyme BACE1 as a therapeutic target for Alzheimer’s disease Robert Vassar* and Patty C Kandalepas en Aβ is secreted from neurons to form amyloid Abstract plaques in the AD brain. Inhibition of β-secretase should Amyloid plaques are de?ning 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 e?cacious for AD, although careful titration of the drug dose may be necessary to limit mechanism-based side e?ects. 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 ? ve 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 p