Recent epidemiological evidence indicates that insulin resistance, a proximal cause of Type II diabetes [a non-insulin dependent form of diabetes mellitus (NIDDM)], is associated with an increased relative risk for Alzheimer's disease (AD). In this study we examined the role of dietary conditions leading to NIDDM-like insulin resistance on amyloidosis in Tg2576 mice, which model AD-like neuropathology. We found that diet-induced insulin resistance promoted amyloidogenic beta-amyloid (Abeta) Abeta1-40 and Abeta1-42 peptide generation in the brain that corresponded with increased gamma-secretase activities and decreased insulin degrading enzyme (IDE) activities. Moreover, increased Abeta production also coincided with increased AD-type amyloid plaque burden in the brain and impaired performance in a spatial water maze task. Further exploration of the apparent interrelationship of insulin resistance to brain amyloidosis revealed a functional decrease in insulin receptor (IR)-mediated signal transduction in the brain, as suggested by decreased IR beta-subunit (IRbeta) Y1162/1163 autophosphorylation and reduced phosphatidylinositol 3 (PI3)-kinase/pS473-AKT/Protein kinase (PK)-B in these same brain regions. This latter finding is of particular interest given the known inhibitory role of AKT/PKB on glycogen synthase kinase (GSK)-3alpha activity, which has previously been shown to promote Abeta peptide generation. Most interestingly, we found that decreased pS21-GSK-3alpha and pS9-GSK-3beta phosphorylation, which is an index of GSK activation, positively correlated with the generation of brain C-terminal fragment (CTF)-gamma cleavage product of amyloid precursor protein, an index of gamma-secretase activity, in the brain of insulin-resistant relative to normoglycemic Tg2576 mice. Our study is consistent with the hypothesis that insulin resistance may be an underlying mechanism responsible for the observed increased relative risk for AD neuropathology, and presents the first evidence to suggest that IR signaling can influence Abeta production in the brain.

Nicotinamide adenine dinucleotide (NAD)؉ -dependent sirtuins have been identified to be key regulators in the lifespan extending effects of calorie restriction (CR) in a number of species. In this study we report for the first time that promotion of the NAD ؉ -dependent sirtuin, SIRT1-mediated deacetylase activity, may be a mechanism by which CR influences Alzheimer disease (AD)-type amyloid neuropathology. Most importantly, we report that the predicted attenuation of ␤-amyloid content in the brain during CR can be reproduced in mouse neurons in vitro by manipulating cellular SIRT1 expression/activity through mechanisms involving the regulation of the serine/threonine Rho kinase ROCK1, known in part for its role in the inhibition of the non-amyloidogenic ␣-secretase processing of the amyloid precursor protein. Conversely, we found that the expression of constitutively active ROCK1 in vitro cultures significantly prevented SIRT1-mediated response, suggesting that ␣-secretase activity is required for SIRT1-mediated prevention of AD-type amyloid neuropathology. Consistently we found that the expression of exogenous human (h) SIRT1 in the brain of hSIRT1 transgenics also resulted in decreased ROCK1 expression and elevated ␣-secretase activity in vivo. These results demonstrate for the first time a role for SIRT1 activation in the brain as a novel mechanism through which CR may influence AD amyloid neuropathology. The study provides a potentially novel pharmacological strategy for AD prevention and/or treatment.Sirtuins are a family of NAD ϩ -dependent histone/protein deacetylases that are highly conserved in their catalytic domains and are distributed across all kingdoms of life (1-4). These enzymes utilize NAD ϩ as a substrate to catalyze deacetylation of specific acetylated-protein substrates (1, 5). Sirtuins can deacetylate a variety of substrates and are, therefore, involved in a broad range of physiological functions, including control of gene expression, metabolism, and aging (6). Accumulating evidence implicates sirtuins in calorie restriction (CR)-mediated health effects including increased organism longevity in yeast, worms, flies, and mammals (1-4, 6). Mammalian genomes encode seven distinct sirtuins (SIRT1-SIRT7). SIRT1 is induced by CR 4 in several tissues and has been implicated in various effects such as stress resistance, reduced apoptosis, and metabolic changes associated with CR (1). SIRT1 is also expressed in the developing and the adult mammalian brain (7). Based on these considerations and on the evidence that CR prevents AD-type amyloid neuropathology in animal models (8, 9), we sought to test the hypothesis that CR may reduce AD-type amyloid neuropathology through mechanisms involving promotion of SIRT1. The relevance of CR treatment in experimental models of AD to human pathology is supported by recent epidemiological evidence suggesting that humans who maintain a low calorie diet have a reduced risk of developing AD (10 -12).Abnormal A␤ deposition within the brain is a hallmark of AD neuropat...

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive impairments in memory and cognition. Extracellular accumulation of soluble high-molecular-weight (HMW) A␤ oligomers has been proposed to be largely responsible for AD dementia and memory deficits in the Tg2576 mice, a model of AD. In this study, we found that a naturally derived grape seed polyphenolic extract can significantly inhibit amyloid ␤-protein aggregation into high-molecular-weight oligomers in vitro. When orally administered to Tg2576 mice, this polyphenolic preparation significantly attenuates AD-type cognitive deterioration coincidentally with reduced HMW soluble oligomeric A␤ in the brain. Our study suggests that grape seed-derived polyphenolics may be useful agents to prevent or treat AD.

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