title: Transcriptional regulation of BACE1 by NFAT3 leads to enhanced amyloidogenic processing.
abstract: Deposition of amyloid β (Aβ) to form neuritic plaques in the brain is the pathological hallmark of Alzheimer's disease (AD). Aβ is generated from sequential cleavages of the β-amyloid precursor protein (APP) by the β- and γ-secretases, and β-site APP-cleaving enzyme 1 (BACE1) is the essential β-secretase for Aβ generation. Vulnerable regions in AD brains show increased BACE1 protein levels. However, the underlying mechanism how BACE1 is regulated remains to be further illustrated. Nuclear Factor of Activated T-cells (NFAT) has been implicated in AD pathogenesis. Despite the increasing appreciation for the importance of NFAT-dependent transcription in the nervous system, the regulation and function of specific NFAT isoforms in neurons is poorly understood. In this report we found that both BACE1 and NFAT3 levels were significantly increased in the brains of APP/PS1 transgenic mice. We found that overexpression of NFAT3 resulted in increase of BACE1 promoter activity and BACE1 transcription, while disruption of NFAT3 expression decreased BACE1 gene transcription and protein expression in SAS1 cells. In a addition, overexpression of NFAT3 leads to increase levels of Aβ production. Chromatin immunoprecipitation analysis revealed direct binding of NFAT3 to specific DNA sequences within BACE1 promoter region. Taken together, our results indicate that NFAT is a BACE1 transcription factor. Our study suggests that inhibition of NFAT-mediated BACE1 expression may be a valuable drug target for AD therapy.
authors: The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, Guangdong Province, People's Republic of China.
authors: Zhengrong
authors: Z
authors: Mei
authors: Pengke
authors: P
authors: Yan
authors: Xiangping
authors: X
authors: Tan
authors: Shiming
authors: S
authors: Zheng
authors: Bing
authors: B
authors: Situ
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic
chemical_list: D000682:Amyloid; D050778:NFATC Transcription Factors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse