Dimeric amyloid β protein rapidly accumulates in lipid rafts followed by apolipoprotein E and phosphorylated tau accumulation in the Tg2576 mouse model of Alzheimer's disease
Dimeric amyloid β protein rapidly accumulates in lipid rafts followed by apolipoprotein E and phosphorylated tau accumulation in the Tg2576 mouse model of Alzheimer's disease
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DOI：
10.1523/jneurosci.5543-03.2004
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发表时间：
2004-04-14
影响因子：
5.3
通讯作者：
Younkin, SG
中科院分区：
文献类型：
--
作者：
Kawarabayashi, T;Shoji, M;Younkin, SG
为了研究脂筏作为淀粉样β蛋白（Abeta）寡聚体可能积聚并导致阿尔茨海默病（AD）毒性的位点，我们分析了Tg 2576转基因AD小鼠模型中的Abeta。Abeta高度浓缩在脂筏中，脂筏占脑体积的一小部分，但在幼龄小鼠中含有27%的脑Abeta 42和24%的Abeta 40。在Tg 2576模型中，记忆障碍在淀粉样蛋白斑块可见之前6个月开始。在这里，我们表明，Abeta二聚体出现在脂筏在6个月，筏Abeta，这主要是二聚体，迅速积累，达到水平>500倍，在年轻的小鼠24-28个月。在来自AD脑的脂筏中观察到二聚体Abeta的类似大量积累。与不溶于SDS的细胞外淀粉样纤维相反，脂筏中几乎所有的Abeta都可溶于SDS。结合最近的研究表明，合成和天然存在的Abeta寡聚体可以抑制海马长时程增强，SDS可溶性Abeta二聚体在Tg 2576小鼠记忆障碍开始时脂筏中的体内年龄依赖性积累提供了将Abeta寡聚体与记忆障碍联系起来的强有力证据。在二聚体Abeta开始在Tg 2576脑的脂筏中积累后，载脂蛋白E（ApoE）和磷酸化tau积累。在AD脑的脂筏中观察到ApoE的类似增加和磷酸化tau的大量增加。这些发现表明，脂筏可能是二聚体Abeta，ApoE和tau之间相互作用的重要位点。
To investigate lipid rafts as a site where amyloid beta protein (Abeta) oligomers might accumulate and cause toxicity in Alzheimer's disease (AD), we analyzed Abeta in the Tg2576 transgenic mouse model of AD.Abeta was highly concentrated in lipid rafts, which comprise a small fraction of brain volume but contain 27% of brain Abeta42 and 24% of Abeta40 in young mice. In the Tg2576 model, memory impairment begins at 6 months before amyloid plaques are visible. Here we show that Abeta dimers appear in lipid rafts at 6 months and that raft Abeta, which is primarily dimeric, rapidly accumulates reaching levels >500 X those in young mice by 24-28 months. A similar large accumulation of dimeric Abeta was observed in lipid rafts from AD brain. In contrast to extracellular amyloid fibrils, which are SDS-insoluble, virtually all Abeta in lipid rafts is SDS soluble. Coupled with recent studies showing that synthetic and naturally occurring Abeta oligomers can inhibit hippocampal long-term potentiation, the in vivo age-dependent accumulation of SDS-soluble Abeta dimers in lipid rafts at the time when memory impairment begins in Tg2576 mice provides strong evidence linking Abeta oligomers to memory impairment. After dimeric Abeta began to accumulate in lipid rafts of the Tg2576 brain, apolipoprotein E (ApoE) and then phosphorylated tau accumulated. A similar increase in ApoE and a large increase in phosphorylated tau was observed in lipid rafts from AD brain. These findings suggest that lipid rafts may be an important site for interaction between dimeric Abeta, ApoE, and tau.