Following activation of the amyloid cascade, apolipoprotein E4 drives the in vivo oligomerization of amyloid-β resulting in neurodegeneration.
Following activation of the amyloid cascade, apolipoprotein E4 drives the in vivo oligomerization of amyloid-β resulting in neurodegeneration.
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DOI：
10.3233/jad-2010-101008
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Michaelson DM
中科院分区：
文献类型：
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作者：
Belinson H;Kariv-Inbal Z;Kayed R;Masliah E;Michaelson DM
根据淀粉样蛋白假说，寡聚化Aβ的积聚是阿尔茨海默病(AD)发病机制中的主要事件。在散发性AD中，最常见的疾病形式-淀粉样蛋白级联和Aβ寡聚的触发机制仍然难以捉摸。在这里，我们检验了一种假说，即载脂蛋白E4(ApoE4)是AD最普遍的遗传风险因素，它在淀粉样级联激活后触发神经元内寡聚Aβ的积累。我们研究了这些过程所针对的细胞内细胞器，并控制了它们的病理后果。这表明，通过抑制Aβ降解酶neprilysin在体内激活淀粉样蛋白级联，特异性地导致Aβ和寡聚化Aβ和apoE4在apoE4小鼠CA1区神经元中积聚。伴随着溶酶体和线粒体的病理改变以及Aβ的共存，Aβ和apoE4与溶酶体增大的寡聚和Aβ的寡聚和Aβ与线粒体的寡聚。溶酶体效应的时间进程与CA1神经元丢失的时间进程平行，而线粒体效应则较早达到平台期。这些发现表明，载脂蛋白E4通过触发Aβ的寡聚化来增强Aβ和淀粉样级联的病理效应，而A DNA的寡聚反过来损害神经元内的线粒体和溶酶体，并推动神经退变。
According to the amyloid hypothesis, the accumulation of oligomerized Aβ is a primary event in the pathogenesis of Alzheimer’s disease (AD). The trigger of the amyloid cascade and of Aβ oligomerization in sporadic AD, the most prevalent form of the disease, remains elusive. Here we examined the hypothesis that apolipoprotein E4 (apoE4), the most prevalent genetic risk factor for AD, triggers the accumulation of intraneuronal oligomerized Aβ following activation of the amyloid cascade. We investigated the intracellular organelles that are targeted by these processes and govern their pathological consequences. This revealed that activation of the amyloid cascade in vivo by inhibition of the Aβ degrading enzyme neprilysin specifically results in accumulation of Aβ and oligomerized Aβ and of apoE4 in CA1 neurons of apoE4 mice. This was accompanied by lysosomal and mitochondrial pathology and the co-localization of Aβ, oligomerized Aβ and apoE4 with enlarged lysosomes and of Aβ and oligomerized Aβ with mitochondria. The time course of the lysosomal effects paralleled that of the loss of CA1 neurons, whereas the mitochondrial effects reached a plateau earlier. These findings suggest that apoE4 potentiates the pathological effects of Aβ and the amyloid cascade by triggering the oligomerization of Aβ, which in turn, impairs intraneuronal mitochondria and lysosomes and drives neurodegeneration.