ABSTRACT
BACKGROUND: Neurofibrillary tangles and senile plaques are hallmarks of Alzheimer's disease (AD) although the molecular basis of their coexistence remains elusive. The peptidyl-prolyl cis/trans isomerase Pin1 acts on both tau and amyloid precursor protein to regulate their functions by influencing tau phosphorylation and amyloid precursor protein processing. OBJECTIVE: In order to identify potential biomarkers for AD in easily accessible cells and to gain insight into the relationship between the brain and peripheral compartments in AD pathology, we investigated Pin1 expression and activity in the peripheral blood mononuclear cells of subjects with late-onset AD (LOAD) and age-matched controls (CT). METHODS: Gene and protein expression, promoter methylation, Ser(16) phosphorylation and activity of Pin1 were evaluated in 32 samples from subjects with LOAD and in 28 samples from CT. RESULTS: In LOAD subjects, there was a statistically significant reduction in Ser(16) phosphorylation (-30%; p = 0.041) and promoter methylation (-8%; p = 0.001), whereas Pin1 expression was significantly increased (+74%; p = 0.018). CONCLUSION: The modifications of Pin1 found in LOAD subjects support its involvement in the pathogenesis of the disease with an important role being played by epigenetic mechanisms.
Subject(s)
Alzheimer Disease/genetics , Epigenesis, Genetic/genetics , Genetic Predisposition to Disease/genetics , Peptidylprolyl Isomerase/genetics , Peptidylprolyl Isomerase/metabolism , Aged , Aged, 80 and over , Alzheimer Disease/pathology , Analysis of Variance , Apolipoprotein E4/genetics , Case-Control Studies , Female , Humans , Italy , Leukocytes, Mononuclear/metabolism , Male , Methylation , NIMA-Interacting Peptidylprolyl Isomerase , Phosphorylation/genetics , Promoter Regions, Genetic/genetics , Serine/metabolismABSTRACT
Neurodegenerative diseases termed Tauopathies, including Alzheimer disease, are characterized by the presence of intraneuronal neurofibrillary tangles (NFTs), composed by hyperphosphorylated protein Tau. Peptidyl-prolyl cis/trans isomerase Pin1 plays a pivotal role in the regulation of Tau phosphorylation/dephosphorylation state. Indeed, Pin1 specifically recognizes pThr231-Pro232 motif of Tau, catalyzes its isomerisation and, in dependence of the cellular environment, promotes its dephosphorylation by PP2A phosphatase: in the dephosphorylated state Tau is able to exert its physiological activity, promoting microtubules polymerization. However, Pin1 activity in Tauopathies in which Tau is mutated can be harmful, because the isomerase can accelerate progression of the disease. Taking into account the complexity of pathways in which Pin1, under a strict regulation, exerts its biological functions, this isomerase can be consider a promising target in the improvement and design of new therapies against Tauopathies.