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.
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Authors | Antonella Caccamo, Caterina Branca, Joshua S Talboom, Darren M Shaw, Dharshaun Turner, Luyao Ma, Angela Messina, Zebing Huang, Jie Wu, Salvatore Oddo |
Journal | The 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 |
PMID | 26468204
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 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
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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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