The transcription factor Yin Yang 1 is an activator of BACE1 expression.
The beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is a prerequisite for the generation of beta-amyloid peptides, the principle constituents of senile plaques in the brains of patients with Alzheimer's disease (AD). BACE1 expression and enzymatic activity are increased in the AD brain, but the regulatory mechanisms of BACE1 expression are largely unknown. Here we show that Yin Yang 1 (YY1), a highly conserved and multifunctional transcription factor, binds to its putative recognition sequence within the BACE1 promoter and stimulates BACE1 promoter activity in rat pheochromocytoma 12 (PC12) cells, rat primary neurones and astrocytes. In rat brain YY1 and BACE1 are widely expressed by neurons, but there was only a minor proportion of neurones that co-expressed YY1 and BACE1, suggesting that YY1 is not required for constitutive neuronal BACE1 expression. Resting astrocytes in the untreated rat brain did not display either YY1 or BACE1 immunoreactivity. When chronically activated, however, astrocytes expressed both YY1 and BACE1 proteins, indicating that YY1 is important for the stimulated BACE1 expression by reactive astrocytes. This is further emphasized by the expression of YY1 and BACE1 by reactive astrocytes in proximity to beta-amyloid plaques in the AD brain. Our observations suggest that interfering with expression, translocation or binding of YY1 to its BACE1 promoter-specific sequence may have therapeutic potential for treating patients with AD.
Paul Flechsig Institute for Brain Research, Department of Neurochemistry, University of Leipzig, Leipzig, Germany.
Katrin
K
Nowak
Christine
C
Lange-Dohna
Ulrike
U
Zeitschel
Albrecht
A
Günther
Bernhard
B
Lüscher
Andrea
A
Robitzki
Regino
R
Perez-Polo
Steffen
S
Rossner
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D016282:Aspartic Acid Endopeptidases; D001253:Astrocytes / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D005911:Gliosis / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000378:metabolism; D016716:PC12 Cells; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding / Q000235:genetics; D051381:Rats; D011918:Rats, Inbred SHR; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics*; D050986:YY1 Transcription Factor / Q000235:genetics* / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D050986:YY1 Transcription Factor; C494700:Yy1 protein, rat; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human