A PIN1 polymorphism that prevents its suppression by AP4 associates with delayed onset of Alzheimer's disease.
Alzheimer's disease (AD), the most common form of dementia, is characterized by the presence of neurofibrillary tangles composed of tau and senile plaques of amyloid-beta peptides (Aβ) derived from amyloid precursor protein (APP). Pin1 is a unique prolyl isomerase that has been shown to protect against age-dependent neurodegeneration by acting on phosphorylated tau and APP to suppress tangle formation and amyloidogenic APP processing. Here we report a functional polymorphism, rs2287839, in the Pin1 promoter that is significantly associated with a 3-year delay in the average age at onset (AAO) of late-onset AD in a Chinese population. More significantly, the Pin1 polymorphism rs2287839 is located within the consensus binding motif for the brain-selective transcription factor, AP4 (CAGCTG) and almost completely abolishes the ability of AP4 to bind and suppress the Pin1 promoter, as shown by chromatin immunoprecipitation, electrophoretic mobility shift assay, and promoter luciferase assay. Moreover, overexpression or knockdown of AP4 resulted in an 80% reduction or 2-fold increase in endogenous Pin1 levels, respectively. Thus, AP4 is a novel transcriptional repressor of Pin1 expression and the Pin1 promoter single nucleotide polymorphism (SNP) identified in this study that prevents such suppression is associated with delayed onset of AD. These results indicate that regulation of Pin1 by AP4 plays a critical role in determining age at onset of AD and might be a novel therapeutic target to delay the onset of AD.
Ma
Suk Ling
SL
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Tang
Nelson Leung Sang
NL
Tam
Cindy Woon Chi
CW
Lui
Victor Wing Cheong
VW
Lam
Linda Chiu Wa
LC
Chiu
Helen Fung Kum
HF
Driver
Jane Ann
JA
Pastorino
Lucia
L
Lu
Kun Ping
KP
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D002461:Cell Line, Transformed; D016009:Chi-Square Distribution; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D055786:Gene Knockout Techniques; D005838:Genotype; D006723:Hong Kong; D006801:Humans; D008297:Male; D008609:Mental Status Schedule; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D019696:Peptidylprolyl Isomerase / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012044:Regression Analysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection
D004268:DNA-Binding Proteins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D034741:RNA, Small Interfering; D014157:Transcription Factors; C055473:enhancer-binding protein AP-4; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase