Altered mitochondria, energy metabolism, voltage-dependent anion channel, and lipid rafts converge to exhaust neurons in Alzheimer's disease
Altered mitochondria, energy metabolism, voltage-dependent anion channel, and lipid rafts converge to exhaust neurons in Alzheimer's disease
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DOI：
10.1007/s10863-009-9243-5
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发表时间：
2009-10-01
影响因子：
3
通讯作者：
Ferrer, Isidre
中科院分区：
文献类型：
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作者：
Ferrer, Isidre
以斑块和淀粉样血管病形式的β-淀粉样蛋白（A β）沉积，以及形成神经纤维缠结、β-淀粉样蛋白斑块周围的营养不良神经突和神经纤维丝的过度磷酸化tau沉积，是阿尔茨海默病（AD）的神经病理学标志，其随着疾病进展在脑中积累。这些变化伴随着突触的逐渐丧失和神经细胞死亡。进行性认知障碍和痴呆是主要的神经功能缺损。此外，有累积的证据表明其他代谢紊乱损害细胞功能和妨碍神经元活力。线粒体的主要成分发生改变：呼吸链的复合物IV减少;代谢ADP形成ATP的复合物V受到氧化损伤和功能改变;电压依赖性阴离子通道VDAC（调节离子通量的线粒体外膜的主要成分）因氧化应激而受损。线粒体是促进对DNA、RNA、蛋白质和脂质的氧化损伤的活性氧的主要来源。氧化损伤的蛋白质靶标是糖酵解、脂质代谢和柠檬酸循环的几种酶组分，这些酶组分为氧化磷酸化、线粒体呼吸和能量产生提供燃料。脂筏的脂质组成、促进底物转移的关键膜特化以及蛋白质-蛋白质和脂质-蛋白质相互作用由于n-3长链多不饱和脂肪酸（主要是二十二碳六烯酸）的异常低水平而改变，所述n-3长链多不饱和脂肪酸（主要是二十二碳六烯酸）增加粘度并增加能量消耗。异常的脂筏组成也可能改变调节淀粉样前体蛋白裂解形成毒性A β的关键酶的活性。在生理条件下，在小窝处参与针对β-淀粉样蛋白的保护的具有雌激素受体α的复合物VDAC的破坏使这进一步复杂化。总之，所有这些改变都集中在改变的细胞中减少的能量产生和增加的能量需求。细胞耗竭被认为是解释神经元功能受损、分子周转减少和细胞死亡增加的决定因素。
beta-amyloid (A beta) deposition, in the form of plaques and amyloid angiopathy, and hyper-phosphorylated tau deposition forming neurofibrillary tangles, dystrophic neurites around beta-amyloid plaques and neuropil threads, are neuropathological hallmarks of Alzheimer's disease (AD) that accumulate in the brain with disease progression. These changes are accompanied by progressive loss of synapses and nerve cell death. Progressive cognitive impairment and dementia are the main neurological deficits. In addition, there is cumulative evidence demonstrating other metabolic disturbances that impair cell function and hamper neuron viability. The main components of the mitochondria are altered: complex IV of the respiratory chain is reduced; complex V which metabolizes ADP to form ATP is oxidatively damaged and functionally altered; and voltage-dependent anion channel VDAC, a major component of the outer mitochondrial membrane that regulates ion fluxes, is damaged as a result of oxidative stress. Mitochondria are a major source of reactive oxygen species that promote oxidative damage to DNA, RNA, proteins and lipids. Protein targets of oxidative damage are, among others, several enzymatic components of the glycolysis, lipid metabolism and cycle of the citric acid that fuel oxidative phosphorylation, mitochondrial respiration and energy production. The lipid composition of lipid rafts, key membrane specializations that facilitate the transfer of substrates, and protein-protein and lipid-protein interactions, is altered as a result of the abnormally low levels of n-3 long chain polyunsaturated fatty acids (mainly docosahexaenoic acid) that increase viscosity and augment energy consumption. Abnormal lipid raft composition may also modify the activity of key enzymes that modulate the cleavage of the amyloid precursor protein to form toxic A beta. This is further complicated by the disruption of the complex VDAC with estrogen receptor alpha at the caveolae which participates, under physiological conditions, in the protection against beta-amyloid. Together, all these alterations converge in reduced energy production and increased energy demands in altered cells. Cell exhaustion is suggested as being a determining element to interpret impaired neuron function, reduced molecular turnover, and enhanced cell death.