Alzheimer's disease (AD) is characterized by the deposition in brain of beta-amyloid (Abeta) peptides, elevated brain caspase-3, and systemic deficiency of cytochrome c oxidase. Although increased Abeta deposition can result from mutations in amyloid precursor protein or presenilin genes, the cause of increased Abeta deposition in sporadic AD is unknown. Cytoplasmic hybrid ("cybrid") cells made from mitochondrial DNA of nonfamilial AD subjects show antioxidant-reversible lowering of mitochondrial membrane potential (delta(gYm), secrete twice as much Abeta(1-40) and Abeta(1-42), have increased intracellular Abeta(1-40) (1.7-fold), and develop Congo red-positive Abeta deposits. Also elevated are cytoplasmic cytochrome c (threefold) and caspase-3 activity (twofold). Increased AD cybrid Abeta(1-40) secretion was normalized by inhibition of caspase-3 or secretase and reduced by treatment with the antioxidant S(-)pramipexole. Expression of AD mitochondrial genes in cybrid cells depresses cytochrome c oxidase activity and increases oxidative stress, which, in turn, lowers delta(psi)m. Under stress, cells with AD mitochondrial genes are more likely to activate cell death pathways, which drive caspase 3-mediated Abeta peptide secretion and may account for increased Abeta deposition in the AD brain. Therapeutic strategies for reducing neurodegeneration in sporadic AD can address restoration of delta(psi)m and reduction of elevated Abeta secretion.

中文翻译：

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阿尔茨海默氏病杂种通过细胞死亡途径复制β-淀粉样蛋白异常。

阿尔茨海默氏病（AD）的特征在于β-淀粉样蛋白（Abeta）肽在大脑中的沉积，脑caspase-3升高和细胞色素c氧化酶的系统性缺乏。尽管淀粉样蛋白前体蛋白或早老素基因的突变可导致Abeta沉积增加，但散发性AD中Abeta沉积增加的原因尚不清楚。由非家族性AD受试者的线粒体DNA制成的细胞质杂种（“杂种”）细胞显示出抗氧化可逆的线粒体膜电位降低（δ（gYm），分泌的Abeta（1-40）和Abeta（1-42）两倍，增加细胞内Abeta（1-40）（1.7倍），并发展刚果红阳性Abeta沉积物，同时提高细胞质的细胞色素c（三倍）和caspase-3活性（两倍）。AD cybrid Abeta（1-40）分泌增加是通过抑制caspase-3或分泌酶来实现的，通过抗氧化剂S（-）普拉克索的处理可以降低其分泌。AD线粒体基因在杂交细胞中的表达降低了细胞色素C氧化酶的活性并增加了氧化应激，进而降低了Δm。在压力下，具有AD线粒体基因的细胞更有可能激活细胞死亡途径，从而驱动caspase 3介导的Abeta肽分泌，并可能解释AD脑中Abeta沉积的增加。减少散发性AD中神经退行性变的治疗策略可以解决delta（psi）m的恢复和升高的Abeta分泌的减少。AD线粒体基因在杂交细胞中的表达降低了细胞色素C氧化酶的活性并增加了氧化应激，进而降低了Δm。在压力下，具有AD线粒体基因的细胞更有可能激活细胞死亡途径，从而驱动caspase 3介导的Abeta肽分泌，并可能解释AD脑中Abeta沉积的增加。减少散发性AD中神经退行性变的治疗策略可以解决delta（psi）m的恢复和升高的Abeta分泌的减少。AD线粒体基因在杂交细胞中的表达降低了细胞色素C氧化酶的活性并增加了氧化应激，进而降低了Δm。在压力下，具有AD线粒体基因的细胞更有可能激活细胞死亡途径，从而驱动caspase 3介导的Abeta肽分泌，并可能解释AD脑中Abeta沉积的增加。减少散发性AD中神经退行性变的治疗策略可以解决delta（psi）m的恢复和升高的Abeta分泌的减少。