BACE1 -: The β-secretase enzyme in Alzheimer's disease

被引:299
作者
Vassar, R [1 ]
机构
[1] Northwestern Univ, Feinberg Sch Med, Dept Cell & Mol Biol, Chicago, IL 60611 USA
关键词
Alzheimer's disease; beta-amyloid; A beta peptide; amyloid precursor protein; beta-secretase; BACE1; BACE2; beta-site APP clearing enzyme;
D O I
10.1385/JMN:23:1-2:105
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Data that have accumulated for well over a decade have implicated the beta-amyloid (Abeta) peptide as a central player in the pathogenesis of Alzheimer's disease (AD). Amyloid plaques, composed primarily of Abeta progressively form in the brains of AD patients, and mutations in three genes (amyloid precursor protein [APP] and presenilin 1 and 2 [PS1 and PS2]) cause early-onset familial AD (FAD) by directly increasing production of the toxic, plaque-promoting Abeta42 peptide. Given the strong association between Abeta and AD, it is likely that therapeutic strategies to lower the levels of Abeta in the brain should prove beneficial for the treatment of AD. One such strategy could involve inhibiting the enzymes that generate Abeta. Abeta is a product of catabolism of the large type-1 membrane protein APP. Two proteases, called beta- and gamma-secretase, endoproteolyze APP to liberate the Abeta peptide. Recently, the molecules responsible for these proteolytic activities have been identified. Several lines of evidence suggest that the PS1 and PS2 proteins are gamma-secretase, and the identity of beta-secretase has been shown to be the novel transmembrane aspartic protease, beta-site APP-cleaving enzyme 1 (BACE1; also called Asp2 and memapsin 2). BACE2, a protease homologous to BACE1, was also identified, and together the two enzymes define a new family of transmembrane aspartic proteases. BACE1 exhibits all the functional properties of 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 recent studies of BACE1 knockout mice that have validated BACE1 as the authentic beta-secretase in vivo.
引用
收藏
页码:105 / 113
页数:9
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[1]   The gene encoding DRAP (BACE2), a glycosylated transmembrane protein of the aspartic protease family, maps to the Down critical region [J].
Acquati, F ;
Accarino, M ;
Nucci, C ;
Fumagalli, P ;
Jovine, L ;
Ottolenghi, S ;
Taramelli, R .
FEBS LETTERS, 2000, 468 (01) :59-64
[2]   Expression analysis of BACE2 in brain and peripheral tissues [J].
Bennett, BD ;
Babu-Khan, S ;
Loeloff, R ;
Louis, JC ;
Curran, E ;
Citron, M ;
Vassar, R .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (27) :20647-20651
[3]   A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer's β-secretase [J].
Bennett, BD ;
Denis, P ;
Haniu, M ;
Teplow, DB ;
Kahn, S ;
Louis, JC ;
Citron, M ;
Vassar, R .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (48) :37712-37717
[4]   A splice variant of β-secretase deficient in the amyloidogenic processing of the amyloid precursor protein [J].
Bodendorf, U ;
Fischer, F ;
Bodian, D ;
Multhaup, G ;
Paganetti, P .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (15) :12019-12023
[5]   Evidence that tumor necrosis factor α converting enzyme is involved in regulated α-secretase cleavage of the Alzheimer amyloid protein precursor [J].
Buxbaum, JD ;
Liu, KN ;
Luo, YX ;
Slack, JL ;
Stocking, KL ;
Peschon, JJ ;
Johnson, RS ;
Castner, BJ ;
Cerretti, DP ;
Black, RA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (43) :27765-27767
[6]   BACE1 is the major β-secretase for generation of Aβ peptides by neurons [J].
Cai, HB ;
Wang, YS ;
McCarthy, D ;
Wen, HJ ;
Borchelt, DR ;
Price, DL ;
Wong, PC .
NATURE NEUROSCIENCE, 2001, 4 (03) :233-234
[7]   Inhibition of amyloid beta-protein production in neural cells by the serine protease inhibitor AEBSF [J].
Citron, M ;
Diehl, TS ;
Capell, A ;
Haass, C ;
Teplow, DB ;
Selkoe, DJ .
NEURON, 1996, 17 (01) :171-179
[8]   GENERATION OF AMYLOID-BETA PROTEIN FROM ITS PRECURSOR IS SEQUENCE-SPECIFIC [J].
CITRON, M ;
TEPLOW, DB ;
SELKOE, DJ .
NEURON, 1995, 14 (03) :661-670
[9]   BACE2, a β-secretase homolog, cleaves at the β site and within the amyloid-β region of the amyloid-β precursor protein [J].
Farzan, M ;
Schnitzler, CE ;
Vasilieva, N ;
Leung, D ;
Choe, H .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (17) :9712-9717
[10]   AMYLOIDOGENESIS IN ALZHEIMERS-DISEASE - SOME POSSIBLE THERAPEUTIC OPPORTUNITIES [J].
GANDY, S ;
GREENGARD, P .
TRENDS IN PHARMACOLOGICAL SCIENCES, 1992, 13 (03) :108-113