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Int J Clin Exp Pathol 2010;3(6):618-628

Review Article
Inhibition of BACE1 for therapeutic use in Alzheimer's disease

Xiaoyang Luo, Riqiang Yan

Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.

Received March 21, 2009; accepted March, 2010; available online March, 2010

Abstract: Since BACE1 was reported as the β-secretase in Alzheimer’s disease (AD) over ten years ago, encouraging progress has been
made toward understanding the cellular functions of BACE1. Genetic studies have further confirmed that BACE1 is essential for processing
amyloid precursor protein (APP) at the β-secretase site. Only after this cleavage can the membrane-bound APP C-terminal fragment be
subsequently cleaved by γ-secretase to release so-called AD-causing Aβ peptides. Hence, in the past decade, a wide variety of BACE1
inhibitors have been developed for AD therapy. This review will summarize the major historical events during the evolution of BACE1 inhibitors
designed through different strategies of drug discovery. Although BACE1 inhibitors are expected to be safe in general, careful titration of drug
dosage to avoid undesirable side effects in BACE1-directed AD therapy is also emphasized. (IJCEP1003010).

Keywords: Alzheimer’s disease, amyloid plaques, BACE1, aspartyl protease, drug discovery

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Address all correspondence to:
Riqiang Yan, PhD
Department of Neurosciences
Lerner Research Institute
The Cleveland Clinic Foundation
9500 Euclid Avenue/NC30
Cleveland, OH 44195, USA.
Tel: 216-445-2690, Fax: 216-444-7927