Rapoport Stanley I
Brain Physiology and Metabolism Sections, Bldg. 10, Rm. 6N202, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
Neurotox Res. 2003;5(6):385-98. doi: 10.1007/BF03033167.
In vivo, post-mortem and biopsy data suggest that coupled declines occur in brain synaptic activity and brain energy consumption during the evolution of Alzheimer disease. In the first stage of these declines, changes in synaptic structure and function reduce neuronal energy demand and lead to potentially reversible downregulation of oxidative phosphorylation (OXPHOS) within neuronal mitochondria. At this stage, measuring brain glucose metabolism or brain blood flow in patients, using positron emission tomography (PET), shows that the brain can be almost normally activated in response to stimulation. Thus, therapy at this stage should be designed to re-establish synaptic integrity or prevent its further deterioration. As disease progresses, neurofibrillary tangles with abnormally phosphorylated tau protein accumulate within neuronal cytoplasm, to the point that they co-opt the nonphosphorylated tau necessary for axonal transport of mitochondria between the cell nucleus and the synapse. In this second stage, severe energy depletion and other pathological processes associated with irreversibly downregulated OXPHOS lead to cell death, and the brain cannot normally respond to functional stimulation.
体内、尸检和活检数据表明，在阿尔茨海默病的发展过程中，大脑突触活动和大脑能量消耗会同时下降。在这些下降的第一阶段，突触结构和功能的变化会降低神经元的能量需求，并导致神经元线粒体内氧化磷酸化（OXPHOS）的潜在可逆性下调。在此阶段，使用正电子发射断层扫描（PET）测量患者的脑葡萄糖代谢或脑血流量，结果显示大脑在受到刺激时几乎可以正常激活。因此，此阶段的治疗应旨在重新建立突触完整性或防止其进一步恶化。随着疾病进展，含有异常磷酸化tau蛋白的神经原纤维缠结在神经元细胞质内积聚，直至它们占用了细胞核与突触之间线粒体轴突运输所需的非磷酸化tau蛋白。在第二阶段，严重的能量消耗以及与OXPHOS不可逆下调相关的其他病理过程会导致细胞死亡，并且大脑无法对功能刺激做出正常反应。
