期刊
JOURNAL OF NEUROSCIENCE
卷 35, 期 41, 页码 14042-14056出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2781-15.2015
关键词
A beta; AD; aging; mTOR; plaques; tangles
资金
- National Institutes of Health [R01 AG037637]
- National Institute of Neurological Disorders and Stroke [U24 NS072026]
- National Institute on Aging [P30 AG19610]
- Arizona Department of Health Services [211002]
- Arizona Biomedical Research Commission [4001, 0011, 05-901, 1001]
- Michael J. Fox Foundation
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-beta and tau, the two neuropathological hallmarks of AD. Mechanistically, these changes were linked to reduced translation of tau and the beta-site amyloid precursor protein cleaving enzyme 1, a key enzyme in the generation of amyloid-beta. 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.
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