Effect of apolipoprotein E allele ε4 on the initial phase of amyloid β-protein accumulation in the human brain
Effect of apolipoprotein E allele ε4 on the initial phase of amyloid β-protein accumulation in the human brain
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DOI：
10.1016/s0002-9440(10)64847-x
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发表时间：
2000-12-01
影响因子：
6
通讯作者：
Ihara, Y
中科院分区：
文献类型：
--
作者：
Morishima-Kawashima, M;Oshima, N;Ihara, Y
淀粉样β蛋白（Aβ）的沉积是阿尔茨海默病的一个标志性特征，在大多数老年人的大脑中都有一定程度的发生。我们试图了解Aβ沉积何时开始，以及载脂蛋白E等位基因ε4（晚发性阿尔茨海默病的一个强风险因素）如何影响沉积。利用一种改进的提取方案和特异性酶联免疫吸附测定法，我们对105例尸检病例大脑不溶性部分中Aβ40和Aβ42的水平进行了定量，这些病例死亡时年龄在22岁至81岁之间，且无痴呆迹象。在所有受检大脑的不溶性部分都检测到了Aβ40和Aβ42；甚至在年仅20 - 30岁的患者大脑中也发现了较低水平的Aβ。显著的Aβ积累发生率随年龄增长而增加，在一些40多岁后期的患者中，Aβ42水平开始急剧上升，同时Aβ40水平的上升幅度要小得多。发现载脂蛋白E ε4等位基因的存在显著促进了Aβ42的积累，在较小程度上也促进了Aβ40的积累。这些发现有力地表明，ε4等位基因的存在导致大脑中Aβ42积累的发病年龄提前。
Deposition of amyloid. beta -protein (A beta), a hallmark of Alzheimer's disease, occurs to some extent in the brains of most elderly individuals. We sought to learn when A beta deposition begins and how deposition is affected by apolipoprotein E allele epsilon4, a strong risk factor for late-onset Alzheimer's disease. Using an improved extraction protocol and specific enzyme-linked immunosorbent assay, we quantified the levels of A beta 40 and A beta 42 in the insoluble fractions of brains from 105 autopsy cases, aged 22 to 81 years at death, who showed no signs of dementia. A beta 40 and A beta 42 were detected in the insoluble fractions from all of the brains examined; low levels were even found in the brains of patients as young as 20 to 30 years of age. The incidence of significant A beta accumulation increased age-dependently, with A beta 42 levels beginning to rise steeply in some patients in their late 40's, accompanied by much smaller increases in A beta 40 levels. The presence of the apolipoprotein E epsilon4 allele was found to significantly enhance the accumulation of A beta 42 and, to a lesser extent, that of A beta 40. These findings strongly suggest that the presence of epsilon4 allele results in an earlier onset of A beta 42 accumulation in the brain.