Reducing Ribosomal Protein S6 Kinase 1 Expression Improves Spatial Memory and Synaptic Plasticity in a Mouse Model of Alzheimer's Disease
| Autor: | Dharshaun Turner, Darren M. Shaw, Antonella Caccamo, Salvatore Oddo, Caterina Branca, Angela Messina, Joshua S. Talboom, Lu-Yao Ma, Zebing Huang, Jie Wu |
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| Rok vydání: | 2015 |
| Předmět: |
Proteasome Endopeptidase Complex
Long-Term Potentiation P70-S6 Kinase 1 Mice Transgenic tau Proteins A beta Hippocampus Ribosomal Protein S6 Kinases 90-kDa Presenilin Amyloid beta-Protein Precursor Mice Alzheimer Disease medicine Amyloid precursor protein Presenilin-1 Animals Aspartic Acid Endopeptidases Humans S6 kinase1 Maze Learning Neurons Memory Disorders Amyloid beta-Peptides Neuronal Plasticity biology General Neuroscience aging Alzheimer mTOR Long-term potentiation Articles medicine.disease Peptide Fragments Disease Models Animal Gene Expression Regulation Ribosomal protein s6 Synaptic plasticity biology.protein Alzheimer's disease Amyloid Precursor Protein Secretases Amyloid precursor protein secretase Neuroscience Locomotion Signal Transduction |
| Popis: | 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 STATEMENTAging 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. |
| Databáze: | OpenAIRE |
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