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PIN1 is an indicator of age‐ and sex‐associated risk of mild cognitive impairment and subsequent Alzheimer’s disease
Author(s) -
Mastroeni Diego F.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.041962
Subject(s) - hyperphosphorylation , pin1 , phosphorylation , disease , psychology , cognitive decline , medicine , oncology , dementia , neuroscience , biology , genetics , gene , isomerase
Abstract Background Women have a higher incidence of Alzheimer’s disease (AD) than men, even after correction for the greater longevity of women. It is also known that AD on the maternal side increases risk for offspring more than does AD on the paternal side. Considerations such as these have led to intense interest in potential molecular differences between the male and female brain, with special emphasis on aging in many studies. Thus, there is an urgent need to identify molecules that identify gender risk early in disease. Excessive post‐translational modifications (e.g. phosphorylation) are known early events in AD. Phosphorylation events are critical intermediates of “normal” protein function, but excessive phosphorylation (e.g. hyperphosphorylation) is unfavorable. Hyperphosphorylation of tau and amyloid triggers the formation of neurofibrillary tangles (NFTs) and toxic Aβ aggregates, both of which have been descried as classical hallmarks of AD. Recent efforts have identified the peptidyl‐prolyl cis/transisomerase (Pin1) as a key regulator of the phosphorylation signaling pathway. Method Here, we demonstrate using Laser Capture micro‐dissection, Affy‐Microarray, RNA sequencing and 450K methylation array that Pin1 is significantly down‐regulated as a function of age (22yrs‐99yrs) and AD, and up‐regulated in MCI limbic and neocortical brain regions. Results Analysis revealed a significant sex and aging effect. In order to confirm, further analysis in a larger AD and matched control cohort (630 patients) from the Religious Orders Study and Memory and Aging Project (ROSMAP) study revealed that the significant decreases in Pin1 levels in AD are wholly driven by female subjects. Conclusion These results set the stage for the development of therapeutic strategies to target Pin1 in females in preclinical AD as a method of preventing, and monitoring the progression of healthy aging to AD.