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 ofβ-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 α-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 α-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 elevatedα-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.

Background: Dietary fibers are metabolized by gastrointestinal (GI) bacteria into short-chain fatty acids (SCFAs). We investigated the potential role of these SCFAs in β-amyloid (Aβ) mediated pathological processes that play key roles in Alzheimer’s disease (AD) pathogenesis. Research design and methods: Multiple complementary assays were used to investigate individual SCFAs for their dose-responsive effects in interfering with the assembly of Aβß1-40 and Aβ1-42 peptides into soluble neurotoxic Aβ aggregates. Results: We found that several select SCFAs are capable of potently inhibiting Aβ aggregations, in vitro. Conclusion: Our studies support the hypothesis that intestinal microbiota may help protect against AD, in part, by supporting the generation of select SCFAs, which interfere with the formation of toxic soluble Aβ aggregates.

Alzheimer disease (AD) is a neurodegenerative disorder of the central nervous system. The neuropathological hallmarks of AD include extracellular amyloid-containing plaques and intracellular neurofibrillary tangles.¹ The molecular events leading to the development of sporadic late-onset AD have not been defined. Advanced age is the largest AD risk factor and glucose/energy metabolism is decreased during aging.^2-7 Recent evidence strongly supports the hypothesis that type 2 diabetes mellitus (T2D) is also a risk factor for AD.^8-11 Moreover, recent evidence suggests that worsening in cerebral glucose metabolism is associated with progression of AD clinical dementia.^12-16