Molecular Biology of Brain Aging and Disease

从不同年龄的健康人和阿尔茨海默病（AD）患者的大脑皮层尸检样品中定量突触完整性和能量代谢的分子指标。在参与突触前和突触后（树突）元素重塑的突触蛋白中发现了显着的年龄下降。AD患者的dreplastin水平降低了81%，dreplastin是一种调节突触后可塑性的蛋白质。AD还与参与氧化磷酸化的线粒体和核酶的活性和基因表达降低有关，氧化磷酸化是以ATP形式产生能量的过程。包括正电子发射（PET）在内的其他证据表明，在AD的早期阶段，这些减少代表脑氧化磷酸化的可逆“下调”。线粒体DNA（mtDNA）的转录显示，使用一个孤立的线粒体转录系统从大鼠肝线粒体，被ADP刺激，但不ATP，并取消由呼吸抑制剂，鱼藤酮。因此，线粒体转录受细胞能量需求的调节，并与呼吸作用相结合。据报道，银杏叶提取物EGb 761对AD有治疗作用。将PC 12细胞暴露于不同浓度的该浸提液长达72 h。北方印迹分析表明，增加的水平的乙醛编码的NADH脱氢酶亚基1（ND 1），这表明EGb 761可以上调线粒体氧化磷酸化。铝与几种神经系统疾病有关，特别是透析性痴呆。 暴露于铝的PC 12细胞在1 μ mol时细胞色素氧化酶亚基III（COXIII）的mRNA减少，这是透析痴呆患者大脑中报告的浓度。 铝的影响是可逆的。 细胞核编码的ND 1 mRNA和12 S rRNA以及细胞核编码的b-肌动蛋白水平不受影响，表明铝选择性靶向考克斯。

Molecular indices of synaptic integrity and energy metabolism were quantified in autopsy samples of cerebral cortex from healthy humans of different ages, and from patients with Alzheimer disease (AD). Significant age declines were found in synaptic proteins involved in remodeling of pre- and postsynaptic (dendritic) elements. AD had an additional 81% decrease in the level of drebrin, a protein regulating postsynaptic plasticity. AD also was associated with reduced activity and gene expression of mitochondrial and nuclear enzymes involved in oxidative phosphorylation, the process by which energy is produced in the form of ATP. Other evidence including positron emission (PET) suggests that, in the early stages of AD, these reductions represent reversible "downregulation" of brain oxidative phosphorylation. Mitochondrial DNA (mtDNA) transcription was shown, using an isolated mitochondrial transcription system from rat liver mitochondria, to be stimulated by ADP but not ATP, and to be abolished by the respiratory inhibitor, rotenone. Thus, mitochondrial transcription is regulated by cellular energy demands and is coupled with respiration. An extract of Ginkgo biloba, EGb 761, is reported to be therapeutic in AD. PC12 cells were exposed to different concentrations of this extract for up to 72 h. Northern blot analysis demonstrated increased levels of the mitochondrial-encoded NADH dehydrogenase subunit 1 (ND1), suggesting that EGb 761 can upregulate mitochondrial oxidative phosphorylation. Aluminum has been implicated in several neurological disorders, particularly dialysis dementia. PC12 cells exposed to aluminum had reduced mRNA for the cytochrome oxidase subunit III (COXIII) at 1 umol, a concentration reported in brains of dialysis dementia patients. The aluminum effect was reversible. Levels of mitochondrially coded ND1 mRNA and 12S rRNA and nuclear encoded b-actin were unaffected, suggesting selective targeting of COX by aluminum.