Transcriptional regulation of beta-secretase by p25/cdk5 leads to enhanced amyloidogenic processing.
Cyclin-dependent kinase 5 (cdk5) has been implicated in Alzheimer's disease (AD) pathogenesis. Here, we demonstrate that overexpression of p25, an activator of cdk5, led to increased levels of BACE1 mRNA and protein in vitro and in vivo. A p25/cdk5 responsive region containing multiple sites for signal transducer and activator of transcription (STAT1/3) was identified in the BACE1 promoter. STAT3 interacts with the BACE1 promoter, and p25-overexpressing mice had elevated levels of pSTAT3 and BACE1, whereas cdk5-deficient mice had reduced levels. Furthermore, mice with a targeted mutation in the STAT3 cdk5 responsive site had lower levels of BACE1. Increased BACE levels in p25 overexpressing mice correlated with enhanced amyloidogenic processing that could be reversed by a cdk5 inhibitor. These data demonstrate a pathway by which p25/cdk5 increases the amyloidogenic processing of APP through STAT3-mediated transcriptional control of BACE1 that could have implications for AD pathogenesis.
Wen
Yi
Y
Taub Institute at Columbia University Medical Center, New York, NY 10032, USA.
Yu
W Haung
WH
Maloney
Bryan
B
Bailey
Jason
J
Ma
Junrong
J
Marié
Isabelle
I
Maurin
Thomas
T
Wang
Lili
L
Figueroa
Helen
H
Herman
Mathieu
M
Krishnamurthy
Pavan
P
Liu
Li
L
Planel
Emmanuel
E
Lau
Lit-Fui
LF
Lahiri
Debomoy K
DK
Duff
Karen
K
D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D051360:Cyclin-Dependent Kinase 5 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D016716:PC12 Cells; D010770:Phosphotransferases; D051381:Rats; D014158:Transcription, Genetic / Q000502:physiology*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C492236:Cdk5r1 protein, mouse; D009419:Nerve Tissue Proteins; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; D053829:Amyloid Precursor Protein Secretases