Abstract
Alzheimer’s Disease (AD) is the most common cause of dementia in the elderly. Centenarians – reaching the age of >100 years while maintaining good cognitive skills – seemingly have unique biological features allowing healthy aging and protection from dementia. Here, we studied the expression of SIRT1 along with miR-132 and miR-212, two microRNAs known to regulate SIRT1, in lymphoblastoid cell lines (LCLs) from 45 healthy donors aged 21 to 105 years and 24 AD patients, and in postmortem olfactory bulb and hippocampus tissues from 14 AD patients and 20 age-matched non-demented individuals. We observed 4.0-fold (P = 0.001) lower expression of SIRT1, and correspondingly higher expression of miR-132 (1.7-fold; P = 0.014) and miR-212 (2.1-fold; P = 0.036), in LCLs from AD patients compared with age-matched healthy controls. Additionally, SIRT1 expression was 2.2-fold (P = 0.001) higher in centenarian LCLs compared with LCLs from individuals aged 56–82 years; while centenarian LCLs miR-132 and miR-212 indicated 7.6-fold and 4.1-fold lower expression, respectively. Correlations of SIRT1, miR-132 and miR-212 expression with cognitive scores were observed for AD patient-derived LCLs and postmortem AD olfactory bulb and hippocampus tissues, suggesting that higher SIRT1 expression, possibly mediated by lower miR-132 and miR-212, may protect aged individuals from dementia and is reflected in their peripheral tissues.
Highlights
With increased longevity in recent decades, humankind is faced with a continued increase in the prevalence of late-onset neurodegenerative disorders, most notably, sporadic Alzheimer’s Disease (AD)
In our recent work[18], we reported reduced expression of SIRT1 (Sirtuin 1) and RGS2 in lymphoblastoid cell lines (LCLs) from AD patients compared with healthy controls
Among genes associated with healthy aging, those coding for sirtuins, NAD+-dependent protein deacylases that cleave off acetyl or other acyl groups from the ε-amino group of lysine residues in histones and other proteins, have received extra attention, as their high expression levels were demonstrated to contribute to longevity and to the lifespan-prolonging effects of caloric restriction in diverse organisms including yeast and mammals[29,30]
Summary
With increased longevity in recent decades, humankind is faced with a continued increase in the prevalence of late-onset neurodegenerative disorders, most notably, sporadic Alzheimer’s Disease (AD). Among genes associated with healthy aging, those coding for sirtuins, NAD+-dependent protein deacylases that cleave off acetyl or other acyl groups from the ε-amino group of lysine residues in histones and other proteins, have received extra attention, as their high expression levels were demonstrated to contribute to longevity and to the lifespan-prolonging effects of caloric restriction in diverse organisms including yeast and mammals[29,30]. Deletion of miR-132 and miR-212 was shown to induce tau aggregation in mice expressing endogenous or human mutant tau[38], and impair mouse cognitive skills[39]. These miRNAs were upregulated in postmortem frontal cortex tissues of AD and mild cognitive impairment (MCI) patients[40]
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