Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction.
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.
Qin
Weiping
W
Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029.
Yang
Tianle
T
Department of Pharmacology, Tri-Institutional Program in Chemical Biology, Weill Medical College of Cornell University, New York, New York 10021.
Ho
Lap
L
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.
Zhao
Zhong
Z
Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029.
Wang
Jun
J
Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029.
Chen
Linghong
L
Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029.
Zhao
Wei
W
Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029.
Thiyagarajan
Meenakshisundaram
M
Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029.
MacGrogan
Donal
D
Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029.
Rodgers
Joseph T
JT
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Puigserver
Pere
P
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Sadoshima
Junichi
J
Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103.
Deng
Haiteng
H
Proteomics Resource Center, The Rockefeller University, New York, New York 10021.
Pedrini
Steven
S
Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, Pennsylvania 19107-5099.
Gandy
Samuel
S
Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, Pennsylvania 19107-5099.
Sauve
Anthony A
AA
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.
Pasinetti
Giulio M
GM
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.
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
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