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Activation of the Wnt/β‐catenin pathway represses the transcription of the β‐amyloid precursor protein cleaving enzyme (BACE1) via binding of T‐cell factor‐4 to BACE1 promoter
Author(s) -
Parr Callum,
Mirzaei Nazanin,
Christian Mark,
Sastre Magdalena
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-253211
Subject(s) - transcription factor , chemistry , catenin , enzyme , wnt signaling pathway , microbiology and biotechnology , tcf4 , transcription (linguistics) , promoter , amyloid precursor protein , gene , biology , biochemistry , gene expression , medicine , linguistics , philosophy , disease , pathology , alzheimer's disease
Alterations in the Wnt signaling pathway have been implicated in Alzheimer's disease; however, its role in the processing of the amyloid precursor protein remains unknown. In this study, activation of the Wnt pathway by overexpression of the agonist Wnt3a or β‐catenin or by inhibition of glycogen kinase synthase‐3 in N2a cells resulted in a reduction in Aβ levels and in the activity and expression of BACE1 (β‐APP cleaving enzyme). Conversely, inhibition of the pathway by transfection of the antagonists secreted frizzled receptor protein‐1 or dickkopf‐1 produced the opposite effects. Chromatin immunoprecipitation analysis demonstrated that β‐catenin binds specifically to regions within the promoter of BACE1 containing putative T‐cell factor/lymphoid enhancer binding factor‐1 (TCF/LEF) motifs, consistent with canonical Wnt target regulation. Furthermore, cells transfected with β‐catenin mutants incapable of binding to TCF/LEF increased BACE1 gene promoter activity. Interestingly, TCF4 knockdown reversed the effects of Wnt3a activation on BACE1 transcription. We found that TCF4 binds to the same region on BACE1 promoter following Wnt3a stimulation, indicating that TCF4 functions as a transcriptional repressor of BACE1 gene. In conclusion, Wnt/β‐catenin stimulation may repress BACE1 transcription via binding of TCF4 to BACE1 gene, and therefore, activation of the Wnt pathway may hold the key to new treatments of Alzheimer disease.—Parr, C., Mirzaei, N., Christian, M., and Sastre, M. Activation of the Wnt/β‐catenin pathway represses the transcription of the β‐amyloid precursor protein cleaving enzyme (BACE1) via binding of T‐cell factor‐4 to BACE1 promoter. FASEB J . 29, 623‐635 (2015). www.fasebj.org