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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.
SIGNIFICANCE STATEMENT:
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.
AuthorsAntonella Caccamo, Caterina Branca, Joshua S Talboom, Darren M Shaw, Dharshaun Turner, Luyao Ma, Angela Messina, Zebing Huang, Jie Wu, Salvatore Oddo
JournalThe Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 35 Issue 41 Pg. 14042-56 (Oct 14 2015) ISSN: 1529-2401 [Electronic] United States
PMID26468204 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 the authors 0270-6474/15/3514042-15$15.00/0.
Chemical References
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • PSEN1 protein, human
  • Peptide Fragments
  • Presenilin-1
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • tau Proteins
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Rps6ka1 protein, mouse
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse
  • Proteasome Endopeptidase Complex
Topics
  • Alzheimer Disease (complications, genetics, pathology)
  • Amyloid Precursor Protein Secretases (metabolism)
  • Amyloid beta-Peptides (metabolism)
  • Amyloid beta-Protein Precursor (genetics)
  • Animals
  • Aspartic Acid Endopeptidases (metabolism)
  • Disease Models, Animal
  • Gene Expression Regulation (genetics, physiology)
  • Hippocampus (pathology)
  • Humans
  • Locomotion (genetics)
  • Long-Term Potentiation (drug effects, genetics)
  • Maze Learning (physiology)
  • Memory Disorders (etiology, therapy)
  • Mice
  • Mice, Transgenic
  • Neuronal Plasticity (genetics, physiology)
  • Neurons (physiology)
  • Peptide Fragments (metabolism)
  • Presenilin-1 (metabolism)
  • Proteasome Endopeptidase Complex (metabolism)
  • Ribosomal Protein S6 Kinases, 90-kDa (genetics, metabolism)
  • Signal Transduction (genetics)
  • tau Proteins (genetics, metabolism)

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