Aging and metabolism-related disorders are risk factors for Alzheimer disease (AD). Since sirtuins may increase the lifespan through regulation of cellular metabolism, we compared the concentration of sirtuin 1 (SIRT1) in the brains of AD patients (n = 19) and controls (n = 22) using Western immunoblots and in situ hybridization. We report a significant reduction of SIRT1 (mRNA: −29%; protein: −45%) in the parietal cortex of AD patients, but not in the cerebellum. Further analyses in a second cohort of 36 subjects confirmed that cortical SIRT1 was decreased in the cortex of AD patients but not in individuals with mild cognitive impairment. SIRT1 mRNA and its translated protein correlated negatively with the duration of symptoms (mRNA: r2 = −0.367; protein: r2 = −0.326) and the accumulation of paired helical filament tau (mRNA: r2 = −0.230; protein: r2 = −0.119), but weakly with insoluble amyloid-β(Aβ42 (mRNA: r2 = −0.090; protein: r2 = −0.072). A significant relationship between SIRT1 levels and global cognition scores proximate to death was also found (r2 = +0.09; p = 0.049). In contrast, cortical SIRT1 levels remained unchanged in a triple-transgenic animal model of AD. Collectively, our results indicate that loss of SIRT1 is closely associated with the accumulation of Aβ and tau in the cerebral cortex of patients with AD.
Defects in insulin production and signaling are suspected to share a key role in diabetes and Alzheimer disease (AD), two age-related pathologies. In this study, we investigated the interrelation between AD and diabetes using a high-fat diet (HFD) in a mouse model of genetically induced AD-like neuropathology (3xTg-AD). We first observed that cerebral expression of human AD transgenes led to peripheral glucose intolerance, associated with pancreatic human Aβ accumulation. High-fat diet enhanced glucose intolerance, brain soluble Aβ, and memory impairment in 3xTg-AD mice. Strikingly, a single insulin injection reversed the deleterious effects of HFD on memory and soluble Aβ levels, partly through changes in Aβ production and/or clearance. Our results are consistent with the development of a vicious cycle between AD and diabetes, potentiating both peripheral metabolic disorders and AD neuropathology. The capacity of insulin to rapidly break the deleterious effects of this cycle on soluble Aβ concentrations and memory has important therapeutic implications.
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