Distinct transcriptional regulation and function of the human BACE2 and BACE1 genes.
Amyloid beta protein (Abeta) is the principal component of neuritic plaques in Alzheimer's disease (AD). Abeta is derived from beta amyloid precursor protein (APP) by beta- and gamma-secretases. Beta-site APP cleaving enzyme 1 (BACE1) has been identified as the major beta-secretase. BACE2 is the homolog of BACE1. The BACE2 gene is on chromosome 21 and has been implicated in the pathogenesis of AD. However, the function of BACE2 in Abeta generation is controversial. Some studies have shown that BACE2 cleaved APP at the beta-site whereas other studies showed it cleaved around the alpha-secretase site. To elucidate the involvement of BACE2 in AD pathogenesis, we compared BACE2 and BACE1 gene regulation and their functions in Abeta generation. We cloned and functionally characterized the human BACE2 promoter. The BACE2 gene is controlled by a TATA-less promoter. Though Sp1 can regulate both BACE1 and BACE2 genes, comparative sequence analysis and transcription factor prediction showed little similarity between the two promoters. BACE1 increased APP cleavage at the beta-site and Abeta production whereas BACE2 did not. Overexpression of BACE2 significantly increased sAPP levels in conditioned media but markedly reduced Abeta production. Knockdown of BACE2 resulted in increased APP C83. Our data indicate that despite being homologous in amino acid sequence, BACE2 and BACE1 have distinct functions and transcriptional regulation. BACE2 is not a beta-secretase, but processes APP within the Abeta domain at a site downstream of the alpha-secretase cleavage site. Our data argue against BACE2 being involved in the formation of neuritic plaques in AD.
Sun
Xiulian
X
Department of Psychiatry, Brain Research Center, The University of British Columbia, Vancouver, BC, Canada.
Wang
Yingcheng
Y
Qing
Hong
H
Christensen
Michelle A
MA
Liu
Yunqiang
Y
Zhou
Weihui
W
Tong
Yigang
Y
Xiao
Cuiying
C
Huang
Yi
Y
Zhang
Sizhong
S
Liu
Xiehe
X
Song
Weihong
W
D000544:Alzheimer Disease / Q000201:enzymology; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000235:genetics* / Q000502:physiology*; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D010450:Endopeptidases / Q000235:genetics* / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008969:Molecular Sequence Data; D009474:Neurons / Q000201:enzymology; D058225:Plaque, Amyloid / Q000201:enzymology; D011401:Promoter Regions, Genetic / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000494:pharmacology / Q000502:physiology; D014158:Transcription, Genetic
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016329:Sp1 Transcription Factor; D004247:DNA; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human