Institut Neuropatologia, Servei Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, CIBERNED, Carrer Feixa LLarga s/n, Hospitalet de LLobregat, Spain.
J Bioenerg Biomembr. 2009 Oct;41(5):425-31. doi: 10.1007/s10863-009-9243-5.
Beta-amyloid (Abeta) 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 Abeta. 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.
β-淀粉样蛋白（Abeta）沉积，以斑块和淀粉样血管病的形式，以及过度磷酸化的 tau 沉积形成神经原纤维缠结、β-淀粉样斑块周围的变性神经突和神经毡纤维，是阿尔茨海默病（AD）的神经病理学标志，随着疾病的进展在大脑中积累。这些变化伴随着突触的逐渐丧失和神经细胞的死亡。进行性认知障碍和痴呆是主要的神经学缺陷。此外，有越来越多的证据表明其他代谢紊乱会损害细胞功能并阻碍神经元存活。线粒体的主要成分发生改变：呼吸链复合物 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，一种调节离子通量的外线粒体膜的主要成分，由于氧化应激而受损。线粒体是活性氧的主要来源，可促进 DNA、RNA、蛋白质和脂质的氧化损伤。氧化损伤的蛋白质靶标除其他外，还有糖酵解、脂质代谢和柠檬酸循环的几种酶促成分，这些酶促成分是氧化磷酸化、线粒体呼吸和能量产生的燃料。脂质筏的脂质组成发生改变，脂质筏是促进底物转移的关键膜特化，以及蛋白质-蛋白质和脂质-蛋白质相互作用发生改变，这是由于 n-3 长链多不饱和脂肪酸（主要是二十二碳六烯酸）的异常低水平引起的，这些脂肪酸增加了粘度并增加了能量消耗。异常的脂质筏组成也可能改变调节淀粉样前体蛋白裂解形成毒性 Abeta 的关键酶的活性。由于雌激素受体α在 caveolae 中断与 VDAC 的复合物，这种情况变得更加复杂，而 caveolae 参与了在生理条件下对β-淀粉样蛋白的保护。所有这些改变都导致能量产生减少和改变细胞的能量需求增加。细胞衰竭被认为是解释神经元功能受损、分子周转率降低和细胞死亡增加的决定性因素。
