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Beta-secretase (BACE) as a drug target for Alzheimer's disease.
Adv Drug Deliv Rev. 2002 Dec 07; 54(12):1589-602.AD

Abstract

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.

Authors+Show Affiliations

Northwestern University Medical School, Department of Cell and Molecular Biology, 303 East Chicago Avenue, Chicago, IL 60611, USA. r-vassar@northwestern.edu

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

12453676

Citation

Vassar, Robert. "Beta-secretase (BACE) as a Drug Target for Alzheimer's Disease." Advanced Drug Delivery Reviews, vol. 54, no. 12, 2002, pp. 1589-602.
Vassar R. Beta-secretase (BACE) as a drug target for Alzheimer's disease. Adv Drug Deliv Rev. 2002;54(12):1589-602.
Vassar, R. (2002). Beta-secretase (BACE) as a drug target for Alzheimer's disease. Advanced Drug Delivery Reviews, 54(12), 1589-602.
Vassar R. Beta-secretase (BACE) as a Drug Target for Alzheimer's Disease. Adv Drug Deliv Rev. 2002 Dec 7;54(12):1589-602. PubMed PMID: 12453676.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Beta-secretase (BACE) as a drug target for Alzheimer's disease. A1 - Vassar,Robert, PY - 2002/11/28/pubmed PY - 2003/6/26/medline PY - 2002/11/28/entrez SP - 1589 EP - 602 JF - Advanced drug delivery reviews JO - Adv Drug Deliv Rev VL - 54 IS - 12 N2 - 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. SN - 0169-409X UR - https://www.unboundmedicine.com/medline/citation/12453676/Beta_secretase__BACE__as_a_drug_target_for_Alzheimer's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0169409X02001576 DB - PRIME DP - Unbound Medicine ER -