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Distinct transcriptional regulation and function of the human BACE2 and BACE1 genes

Xiulian Sun^*,,1, Yingcheng Wang^*,,1, Hong Qing^*, Michelle A. Christensen^*, Yunqiang Liu, Weihui Zhou^*, Yigang Tong^*, Cuiying Xiao, Yi Huang, Sizhong Zhang, Xiehe Liu and Weihong Song^*,,2

^* Department of Psychiatry, Brain Research Center,
Graduate Program in Neuroscience, The University of British Columbia, Vancouver, BC, Canada; and
Department of Psychiatry,
Department of Medical Genetics, West China Hospital and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, China

² Correspondence: Department of Psychiatry, The University of British Columbia, Vancouver, BC V6T 1Z3, Canada. E-mail: weihong{at}interchange.ubc.ca

Amyloid ß protein (Aß) is the principal component of neuritic plaques in Alzheimer’s disease (AD). Aß is derived from ß amyloid precursor protein (APP) by ß- and -secretases. Beta-site APP cleaving enzyme 1 (BACE1) has been identified as the major ß-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 Aß generation is controversial. Some studies have shown that BACE2 cleaved APP at the ß-site whereas other studies showed it cleaved around the -secretase site. To elucidate the involvement of BACE2 in AD pathogenesis, we compared BACE2 and BACE1 gene regulation and their functions in Aß 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 ß-site and Aß production whereas BACE2 did not. Overexpression of BACE2 significantly increased sAPP levels in conditioned media but markedly reduced Aß 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 ß-secretase, but processes APP within the Aß domain at a site downstream of the -secretase cleavage site. Our data argue against BACE2 being involved in the formation of neuritic plaques in AD.—Sun, X., Wang, Y., Qing, H., Christensen, M. A., Liu, Y., Zhou, W., Tong, Y., Xiao, C., Huang, Y., Zhang, S., Liu, X., Song, W. Distinct transcriptional regulation and function of the human BACE2 and BACE1 genes.

Key Words: secretase • amyloid ß • transcription • promoter • Alzheimer’s disease

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