title: Reducing Ribosomal Protein S6 Kinase 1 Expression Improves Spatial Memory and Synaptic Plasticity in a Mouse Model of Alzheimer's Disease.
abstract: Aging is the most important risk factor associated with Alzheimer's disease (AD); however, the molecular mechanisms linking aging to AD remain unclear. Suppression of the ribosomal protein S6 kinase 1 (S6K1) increases healthspan and lifespan in several organisms, from nematodes to mammals. Here we show that S6K1 expression is upregulated in the brains of AD patients. Using a mouse model of AD, we found that genetic reduction of S6K1 improved synaptic plasticity and spatial memory deficits, and reduced the accumulation of amyloid-β and tau, the two neuropathological hallmarks of AD. Mechanistically, these changes were linked to reduced translation of tau and the β-site amyloid precursor protein cleaving enzyme 1, a key enzyme in the generation of amyloid-β. Our results implicate S6K1 dysregulation as a previously unidentified molecular mechanism underlying synaptic and memory deficits in AD. These findings further suggest that therapeutic manipulation of S6K1 could be a valid approach to mitigate AD pathology.
  
  
  CONCLUSIONS
  Aging is the most important risk factor for Alzheimer's disease (AD). However, little is known about how it contributes to AD pathogenesis. S6 kinase 1 (S6K1) is a protein kinase involved in regulation of protein translation. Reducing S6K1 activity increases lifespan and healthspan. We report the novel finding that reducing S6K1 activity in 3xTg-AD mice ameliorates synaptic and cognitive deficits. These improvement were associated with a reduction in amyloid-β and tau pathology. Mechanistically, lowering S6K1 levels reduced translation of β-site amyloid precursor protein cleaving enzyme 1 and tau, two key proteins involved in AD pathogenesis. These data suggest that S6K1 may represent a molecular link between aging and AD. Given that aging is the most important risk factor for most neurodegenerative diseases, our results may have far-reaching implications into other diseases.
authors.affiliation: Banner Sun Health Research Institute, Sun City, Arizona 85351, Department of Biological, Geological and Environmental Sciences, University of Catania, 95125 Catania, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Caccamo
authors.affiliation: Banner Sun Health Research Institute, Sun City, Arizona 85351, Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona 85004.
authors.forename: Caterina
authors.initials: C
authors.lastname: Branca
authors.affiliation: Banner Sun Health Research Institute, Sun City, Arizona 85351.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Talboom
authors.affiliation: Banner Sun Health Research Institute, Sun City, Arizona 85351.
authors.forename: Darren M
authors.initials: DM
authors.lastname: Shaw
authors.affiliation: Divisions of Neurology and Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013, and.
authors.forename: Dharshaun
authors.initials: D
authors.lastname: Turner
authors.affiliation: Divisions of Neurology and Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013, and.
authors.forename: Luyao
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Biological, Geological and Environmental Sciences, University of Catania, 95125 Catania, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Messina
authors.affiliation: Divisions of Neurology and Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013, and.
authors.forename: Zebing
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Divisions of Neurology and Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013, and Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona 85004.
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.affiliation: Banner Sun Health Research Institute, Sun City, Arizona 85351, Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona 85004 oddo@email.arizona.edu.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Oddo
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008124:Locomotion / Q000235:genetics; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000209:etiology / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1 / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D046988:Proteasome Endopeptidase Complex
keywords: AD; Aβ; aging; mTOR; plaques; tangles