Neuronal SIRT1 Activation as a Novel Mechanism Underlying the Prevention of Alzheimer Disease Amyloid Neuropathology by Calorie Restriction*

By W. Qin, Tianle Yang, L. Ho, Zhong Zhao, Jun Wang, Linghong Chen, Wei Zhao, M. Thiyagarajan, D. MacGrogan, J. T. Rodgers and 7 more. Journal of Biological Chemistry, 2006

629 citations recorded by the source corpus.

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.

Subfields: Cell Biology, Geriatrics and Gerontology, Physiology

View Paper: https://www.semanticscholar.org/paper/e8f4fe53ba44c8838e1c1d778f9ccfcbf09607ac

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Citations in the corpus

Age Related Changes in NAD+ Metabolism Oxidative Stress and Sirt1 Activity in Wistar Rats (2011, background): “Sirt1 is the human homolog of sir2 and appears to be involved in several physiological functions including the control of gene expression, cell cycle regulation, apoptosis, DNA repair, metabolism, and aging [31,32,33].”
SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis (2007, methodology): “A ratio neurons control side/neurons SIRT1 side was calculated to quantify variations in percentage of neurons between both sides.”
Cellular Stress Responses, The Hormesis Paradigm, and Vitagenes: Novel Targets for Therapeutic Intervention in Neurodegenerative Disorders (2010, positive): “All these effects were totally reversible after H 2 S washout, with animals showing a complete recovery and normal behavior (363).”
SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function (2012, background): “…many of the salutary effects of CR, including a reduced incidence of cardiovascular and metabolic diseases (Banks et al., 2008; Bordone et al., 2007; Pfluger et al., 2008), cancer (Herranz et al., 2010; Oberdoerffer et al., 2008), and neurodegeneration (Donmez et al., 2010; Qin et al., 2006).”
NAD+ metabolism and the control of energy homeostasis - a balancing act between mitochondria and the nucleus (2015, background): “This, in turn, limits NAD+ availability for other nuclear enzymes such as SIRT1 (Figure 3A) (Bai et al., 2011b; Pillai et al., 2005; Qin et al., 2006; Rajamohan et al., 2009).”
The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. (2010, background): “ActivationofSIRT1inmodels forthese diseases was shown to significantly improve the pathology (223, 224).”
Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC‐1α (2007, background): “In addition, in neuronal cells, caloric restriction also regulates endo- genous levels of nicotinamide (Qin et al, 2006).”