Beta-secretase (BACE) as a drug target for Alzheimer's disease.
Evidence suggests that the beta-amyloid peptide (Abeta) is central to the pathophysiology of Alzheimer's Disease (AD). Amyloid plaques, primarily composed of Abeta, progressively develop in the brains of AD patients, and mutations in three genes (APP, PS1, and PS2) cause early on-set familial AD (FAD) by increasing synthesis of the toxic Abeta42 peptide. Given the strong association between Abeta and AD, therapeutic strategies to lower the concentration of Abeta in the brain should prove beneficial for the treatment of AD. Abeta is a proteolytic product of the large TypeI membrane protein, amyloid precursor protein (APP). Two proteases, called beta- and gamma-secretase, cleave APP to generate the Abeta peptide. For over a decade, the molecular identities of these proteases were unknown. Recently, the gamma-secretase has been tentatively identified as the presenilin proteins, PS1 and PS2, and the beta-secretase has been shown to be the novel transmembrane aspartic protease, beta-site APP Cleaving Enzyme 1 (BACE1; also called Asp2 and memapsin2). BACE2, a novel protease homologous to BACE1, was also identified, and the two BACE enzymes define a new family of transmembrane aspartic proteases. BACE1 exhibits all the properties of the beta-secretase, and as the key enzyme that initiates the formation of Abeta, BACE1 is an attractive drug target for AD. This review discusses the identification and initial characterization of BACE1 and BACE2, and summarizes our current understanding of BACE1 post-translational processing and intracellular trafficking. Finally, recent studies of BACE1 knockout mice, the BACE1 X-ray structure, and implications for BACE1 drug development will be discussed.
Vassar
Robert
R
Northwestern University Medical School, Department of Cell and Molecular Biology, 303 East Chicago Avenue, Chicago, IL 60611, USA. r-vassar@northwestern.edu
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology*; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D010450:Endopeptidases; D006801:Humans; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use
D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human