ABSTRACT
Alzheimer's disease (AD) is a common neurodegenerative disorder, strongly related with age. It has been reported that genetic variants of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2), a cell-surface receptor expressed in microglial cells, greatly increase the risk of AD, thus suggesting an involvement of the microglia in the AD pathogenesis. The aim of this report is to provide an overview of the TREM2 and of its possible implication in the pathogenesis of AD.
Subject(s)
Alzheimer Disease/pathology , Membrane Glycoproteins/metabolism , Microglia/metabolism , Receptors, Immunologic/metabolism , Alzheimer Disease/metabolism , Biomarkers/metabolism , Humans , Membrane Glycoproteins/genetics , Receptors, Immunologic/genetics , RiskABSTRACT
INTRODUCTION: The genetic background plays a role on longevity. The distribution of the apolipoprotein E gene (APOE) variants (ε2, ε3, ε4) may differ across age groups, especially in the oldest old and despite geographical and ethnic specificities. Since the ε4 variant is associated with Alzheimer's disease (AD), it might represent an opportunity for exploring the relationship of APOE with physiological and pathological aging. AIM: To explore the role played by APOE genotype/alleles on physiological and pathological brain aging. MATERIALS AND METHODS: The study was conducted in a cohort of centenarians (n = 106), and two cohorts of octogenarians (without cognitive decline, n = 351 controls; and with AD, n = 294). RESULTS: No significant differences in genotype/allele distributions were observed comparing controls to centenarians. The prevalence of ε2/ε3, ε3/ε3, ε3/ε4 and ε4/ε4 genotypes were significantly different in centenarians compared to AD. The prevalence of ε2 and ε3 alleles were significantly higher in centenarians, whereas the ε4 was less frequent. The ε4 allele was positively associated with AD, whereas a negative association was found for ε2 and ε3 alleles. CONCLUSIONS: Our study indicates that ε4 allele is strongly associated with AD. APOE significantly affects AD risk, but apparently not longevity.
Subject(s)
Aging/genetics , Apolipoprotein E2/genetics , Apolipoprotein E3/genetics , Apolipoprotein E4/genetics , Healthy Aging/genetics , Aged , Aged, 80 and over , Alleles , Alzheimer Disease/blood , Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/genetics , Cohort Studies , Female , Genotype , Humans , Logistic Models , Longevity/genetics , Male , Polymorphism, Genetic , Registries/statistics & numerical dataABSTRACT
BACKGROUND AND PURPOSE: Neuroinflammation plays a role in the aetiopathogenesis of Alzheimer's disease (AD). Triggering receptor expressed on myeloid cells 2 (TREM2), a cell surface receptor of the immunoglobulin superfamily, seems to have protective anti-inflammatory activity in AD. METHODS: Triggering receptor expressed on myeloid cells 2 expression was analysed in peripheral blood mononuclear cells from healthy subjects (CT) and from patients with either AD or mild cognitive impairment (MCI). MCI patients were re-evaluated at a 2-year follow-up to investigate their progression to AD (MCI-AD) or lack thereof (MCI-MCI). RESULTS: Triggering receptor expressed on myeloid cells 2 gene expression was higher in AD than CT patients, but was highest in MCI. At recruitment TREM2 levels were higher in MCI-AD than in MCI-MCI, and in MCI-AD were higher initially than at follow-up. TREM2 displayed a moderate degree of sensitivity and specificity for identifying MCI-AD in all MCI patients. Our data showed higher TREM2 levels in allele ε4 of apolipoprotein E (ApoE ε4) carriers than non-carriers in MCI and particularly in MCI-AD. CONCLUSIONS: These data seem to confirm the protective role of TREM2 in the pre-clinical stage of AD. Upregulation of TREM2 in MCI-AD could be a mechanism to counteract the activation of neuroinflammatory processes. It is possible that TREM2 and ApoE ε4 interact synergistically in the pre-clinical stage of AD. Therefore, TREM2 may be useful as an early peripheral biomarker for the development of AD.
Subject(s)
Alzheimer Disease/metabolism , Cognitive Dysfunction/metabolism , Leukocytes, Mononuclear/metabolism , Membrane Glycoproteins/metabolism , Receptors, Immunologic/metabolism , Aged , Aged, 80 and over , Alzheimer Disease/etiology , Biomarkers/metabolism , Cognitive Dysfunction/complications , Disease Progression , Female , Follow-Up Studies , Humans , MaleABSTRACT
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.
