载脂蛋白E异构体依赖性淀粉样蛋白沉积及阿尔茨海默病小鼠模型中的神经突退变
Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease.
作者信息
Holtzman D M, Bales K R, Tenkova T, Fagan A M, Parsadanian M, Sartorius L J, Mackey B, Olney J, McKeel D, Wozniak D, Paul S M
机构信息
Department of Neurology, Center for the Study of Nervous System Injury, Washington University School of Medicine, 660 South Euclid Avenue, Box 8111, St. Louis, MO 63110, USA.
出版信息
Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2892-7. doi: 10.1073/pnas.050004797.
Apolipoprotein E (apoE) alleles determine the age-adjusted relative risk (epsilon4 > epsilon3) for Alzheimer's disease (AD). ApoE may affect AD pathogenesis by promoting deposition of the amyloid-beta (Abeta) peptide and its conversion to a fibrillar form. To determine the effect of apoE on Abeta deposition and AD pathology, we compared APP(V717F) transgenic (TG) mice expressing mouse, human, or no apoE (apoE(-/-)). A severe, plaque-associated neuritic dystrophy developed in APP(V717F) TG mice expressing mouse or human apoE. Though significant levels of Abeta deposition also occurred in APP(V717F) TG, apoE(-/-) mice, neuritic degeneration was virtually absent. Expression of apoE3 and apoE4 in APP(V717F) TG, apoE(-/-) mice resulted in fibrillar Abeta deposits and neuritic plaques by 15 months of age and substantially (>10-fold) more fibrillar deposits were observed in apoE4-expressing APP(V717F) TG mice. Our data demonstrate a critical and isoform-specific role for apoE in neuritic plaque formation, a pathological hallmark of AD.
载脂蛋白E（apoE）等位基因决定了阿尔茨海默病（AD）经年龄调整后的相对风险（ε4 > ε3）。载脂蛋白E可能通过促进β淀粉样蛋白（Aβ）肽的沉积及其向纤维状形式的转化来影响AD的发病机制。为了确定载脂蛋白E对Aβ沉积和AD病理的影响，我们比较了表达小鼠、人类载脂蛋白E或不表达载脂蛋白E（apoE-/-）的APP（V717F）转基因（TG）小鼠。在表达小鼠或人类载脂蛋白E的APP（V717F）转基因小鼠中出现了严重的、与斑块相关的神经炎性营养不良。虽然在APP（V717F）转基因、apoE-/-小鼠中也发生了显著水平的Aβ沉积，但几乎没有神经变性。在APP（V717F）转基因、apoE-/-小鼠中表达apoE3和apoE4，到15月龄时会导致纤维状Aβ沉积和神经炎性斑块，并且在表达apoE4的APP（V717F）转基因小鼠中观察到的纤维状沉积物要多得多（>10倍）。我们的数据证明了载脂蛋白E在神经炎性斑块形成（AD的一个病理标志）中起关键且异构体特异性的作用。
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