Molecular Biology of Brain Aging and Disease

对不同年龄段健康人和阿尔茨海默病(AD)患者大脑皮层解剖标本中突触完整性和能量代谢的分子指标进行了量化。与突触前和突触后(树突状)成分重塑有关的突触蛋白的年龄显著下降。AD患者的突触后可塑性调节蛋白Drebrin的水平又下降了81%。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的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，在阿尔茨海默病的早期阶段，这些减少代表着大脑氧化磷酸化的可逆“下调”。利用分离的大鼠肝线粒体线粒体转录系统，发现线粒体DNA(MtDNA)转录可被ADP刺激，但不能被ATP刺激，并可被呼吸抑制剂鱼藤酮取消。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。银杏叶提取物，据报道对阿尔茨海默病有治疗作用。将不同浓度的银杏叶提取物作用于PC12细胞72h，Northern印迹分析显示线粒体编码的NADH脱氢酶亚单位1(ND1)表达增加，提示银杏叶提取物可上调线粒体氧化磷酸化水平。铝与几种神经疾病有关，特别是透析痴呆症。暴露于铝的PC12细胞在1umol时细胞色素氧化酶亚基III(COXIII)的mRNA减少，据报道，这一浓度在透析痴呆患者的大脑中。铝效应是可逆的。线粒体编码的ND1mRNA、12S rRNA和核编码的b-肌动蛋白的水平没有受到影响，这表明铝有选择性地靶向COX。

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.