Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease
Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease
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DOI：
10.1073/pnas.050004797
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发表时间：
2000-03-14
影响因子：
11.1
通讯作者：
Paul, SM
中科院分区：
文献类型：
--
作者：
Holtzman, DM;Bales, KR;Paul, SM
载脂蛋白E（apoE）等位基因决定了阿尔茨海默病（AD）的年龄校正相对危险度（104> 103）。ApoE可能通过促进淀粉样蛋白-β（A β）肽的沉积及其转化为纤维状形式来影响AD发病机制。为了确定apoE对A β沉积和AD病理学的影响，我们比较了表达小鼠、人或无apoE（apoE（-/-））的App（V717F）转基因（TG）小鼠。在表达小鼠或人apoE的App（V717 F）TG小鼠中发生的严重斑块相关神经炎性营养不良虽然在App（V717F）TG、apoE（-/-）小鼠中也发生了显著水平的A β沉积，但几乎不存在神经炎变性。apoE（-/-）小鼠在15个月大时导致纤维状A β沉积和神经炎斑块，在表达apoE4的App（V717 F）TC小鼠中观察到更多（> 10倍）的纤维沉积。我们的数据表明，在神经炎斑块形成，AD的病理标志，apoE的关键和亚型特异性的作用。
Apolipoprotein E (apoE) alleles determine the age-adjusted relative risk (epsilon 4 > epsilon 3) for Alzheimer's disease (AD). ApoE may affect AD pathogenesis by promoting deposition of the amyloid-beta (A beta) peptide and its conversion to a fibrillar form. To determine the effect of apoE on A beta 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 A beta 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 A beta deposits and neuritic plaques by 15 months of age and substantially (> 10-fold) more fibrillar deposits were observed in apoE4-expressing App(V717F) TC mice. Our data demonstrate a critical and isoform-specific role for apoE in neuritic plaque formation, a pathological hallmark of AD.