早老素
神经退行性变
氧化应激
程序性细胞死亡
线粒体
β淀粉样蛋白
淀粉样前体蛋白
生物
阿尔茨海默病
细胞色素c
分泌物
细胞内
分子生物学
化学
细胞生物学
细胞凋亡
内科学
内分泌学
生物化学
医学
肽
疾病
作者
Khan Sm,Cassarino Ds,Abramova Nn,Keeney Pm,Borland Mk,Trimmer Pa,Krebs Ct,Bennett Jc,Parks Jk,Swerdlow Rh,Parker Wd,Bennett Jp
出处
期刊:PubMed
日期:2000-08-01
卷期号:48 (2): 148-55
被引量:79
摘要
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.
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