Neuropharmacology and Neurobiology, College of Medical and Dental Sciences, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK.
Acta Neuropathol Commun. 2013 May 8;1:3. doi: 10.1186/2051-5960-1-3.
The development of disease-modifying therapies for Alzheimer's disease is hampered by our lack of understanding of the early pathogenic mechanisms and the lack of early biomarkers and risk factors.We have documented the expression pattern of mTOR regulated genes in the frontal cortex of Alzheimer's disease patients. We have also examined the functional integrity of mTOR signaling in peripheral lymphocytes in Alzheimer's disease patients relative to healthy controls.
In the brain mTOR is seen to control molecular functions related to cell cycle regulation, cell death and several metabolic pathways. These downstream elements of the mTOR signaling cascade are deregulated in the brain of Alzheimer's disease patients well before the development of pathology. This dysregulation of the mTOR downstream signaling cascade is not restricted to the brain but appears to be systemic and can be detected in peripheral lymphocytes as a reduced Rapamycin response.
The dysfunction of the signaling pathways downstream of mTOR may represent a risk factor for Alzheimer's disease and is independent of the ApoE status of the patients.We have also identified the molecular substrates of the beneficial effects of Rapamycin on the nervous system. We believe that these results can further inform the development of clinical predictive tests for the risk of Alzheimer's disease in patients with mild cognitive impairment.
由于我们对阿尔茨海默病的早期发病机制缺乏了解，也缺乏早期生物标志物和风险因素，因此疾病修饰疗法的发展受到了阻碍。我们已经记录了阿尔茨海默病患者大脑皮质中 mTOR 调节基因的表达模式。我们还研究了阿尔茨海默病患者与健康对照组外周血淋巴细胞中 mTOR 信号通路的功能完整性。
mTOR 在大脑中被认为控制与细胞周期调控、细胞死亡和几种代谢途径相关的分子功能。阿尔茨海默病患者大脑中 mTOR 信号级联的这些下游元件在病理学发展之前就已经失调。mTOR 下游信号级联的这种失调不仅限于大脑，而且似乎是全身性的，可以在外周血淋巴细胞中检测到雷帕霉素反应降低。
mTOR 信号通路下游的功能障碍可能代表阿尔茨海默病的一个风险因素，并且与患者的 ApoE 状态无关。我们还确定了雷帕霉素对神经系统有益作用的分子底物。我们相信，这些结果可以进一步为轻度认知障碍患者的阿尔茨海默病风险提供临床预测测试的开发依据。
