title: Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction.
abstract: 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 beta-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 alpha-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 alpha-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 alpha-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.
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029.
authors.forename: Weiping
authors.initials: W
authors.lastname: Qin
authors.affiliation: Department of Pharmacology, Tri-Institutional Program in Chemical Biology, Weill Medical College of Cornell University, New York, New York 10021.
authors.forename: Tianle
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029; Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029; Geriatric Research and Clinical Center, Bronx Veterans Affairs Medical Center, Bronx, New York 10468.
authors.forename: Lap
authors.initials: L
authors.lastname: Ho
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029.
authors.forename: Linghong
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029.
authors.forename: Meenakshisundaram
authors.initials: M
authors.lastname: Thiyagarajan
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029.
authors.forename: Donal
authors.initials: D
authors.lastname: MacGrogan
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Rodgers
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Pere
authors.initials: P
authors.lastname: Puigserver
authors.affiliation: Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103.
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
authors.affiliation: Proteomics Resource Center, The Rockefeller University, New York, New York 10021.
authors.forename: Haiteng
authors.initials: H
authors.lastname: Deng
authors.affiliation: Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, Pennsylvania 19107-5099.
authors.forename: Steven
authors.initials: S
authors.lastname: Pedrini
authors.affiliation: Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, Pennsylvania 19107-5099.
authors.forename: Samuel
authors.initials: S
authors.lastname: Gandy
authors.affiliation: Department of Pharmacology, Tri-Institutional Program in Chemical Biology, Weill Medical College of Cornell University, New York, New York 10021. Electronic address: as2004@med.cornell.edu.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Sauve
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029; Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029; Geriatric Research and Clinical Center, Bronx Veterans Affairs Medical Center, Bronx, New York 10468. Electronic address: giulio.pasinetti@mssm.edu.
authors.forename: Giulio M
authors.initials: GM
authors.lastname: Pasinetti
mesh_terms: D000544:Alzheimer Disease / Q000178:diet therapy* / Q000517:prevention & control; D000682:Amyloid / Q000032:analysis; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D031204:Caloric Restriction; D010450:Endopeptidases / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism*; D054460:rho-Associated Kinases
chemical_list: D000682:Amyloid; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; C515851:ROCK1 protein, human; C515854:Rock1 protein, mouse; D054460:rho-Associated Kinases; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins