Caccamo Antonella, Branca Caterina, Talboom Joshua S, Shaw Darren M, Turner Dharshaun, Ma Luyao, Messina Angela, Huang Zebing, Wu Jie, Oddo Salvatore
Banner Sun Health Research Institute, Sun City, Arizona 85351, Department of Biological, Geological and Environmental Sciences, University of Catania, 95125 Catania, Italy.
Banner Sun Health Research Institute, Sun City, Arizona 85351, Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona 85004.
J Neurosci. 2015 Oct 14;35(41):14042-56. doi: 10.1523/JNEUROSCI.2781-15.2015.
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.
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.
衰老 是与阿尔茨海默病（AD）相关的最重要风险因素；然而，将衰老与AD联系起来的分子机制仍不清楚。抑制核糖体蛋白S6激酶1（S6K1）可延长从线虫到哺乳动物等多种生物体的健康寿命和寿命。在此，我们表明AD患者大脑中S6K1的表达上调。使用AD小鼠模型，我们发现基因敲低S6K1可改善突触可塑性和空间记忆缺陷，并减少淀粉样β蛋白和tau蛋白的积累，这是AD的两个神经病理学特征。从机制上讲，这些变化与tau蛋白和β位点淀粉样前体蛋白裂解酶1（淀粉样β蛋白生成中的关键酶）的翻译减少有关。我们的结果表明，S6K1失调是AD中突触和记忆缺陷背后一种先前未被识别的分子机制。这些发现进一步表明，对S6K1进行治疗性调控可能是减轻AD病理的有效方法。
衰老 是阿尔茨海默病（AD）最重要的风险因素。然而，对于它如何导致AD发病机制却知之甚少。S6激酶1（S6K1）是一种参与蛋白质翻译调控的蛋白激酶。降低S6K1活性可延长寿命和健康寿命。我们报告了一项新发现，即降低3xTg-AD小鼠中的S6K1活性可改善突触和认知缺陷。这些改善与淀粉样β蛋白和tau蛋白病理的减少有关。从机制上讲，降低S6K1水平可减少β位点淀粉样前体蛋白裂解酶1和tau蛋白的翻译，这两种关键蛋白参与AD发病机制。这些数据表明，S6K1可能代表衰老与AD之间的分子联系。鉴于衰老 是大多数神经退行性疾病最重要的风险因素，我们的结果可能对其他疾病具有深远影响。
