Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid β peptide.
Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid β peptide.
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DOI：
10.1523/jneurosci.1542-12.2012
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发表时间：
2012-10-24
期刊：
影响因子：
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通讯作者：
Hyman BT
中科院分区：
文献类型：
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作者：
Hashimoto T;Serrano-Pozo A;Hori Y;Adams KW;Takeda S;Banerji AO;Mitani A;Joyner D;Thyssen DH;Bacskai BJ;Frosch MP;Spires-Jones TL;Finn MB;Holtzman DM;Hyman BT
阿尔茨海默病(AD)是导致痴呆的最常见的进行性神经退行性疾病。淀粉样蛋白β肽(Aβ)作为老年斑在脑内大量沉积是AD的病理特征，但Aβ的寡聚体、可溶性形式被认为是突触毒性成分。载脂蛋白E epsilon 4(apoEε4)等位基因是阿尔茨海默病的遗传危险因素。然而，目前尚不清楚载脂蛋白E如何影响Aβ齐聚过程。在这里，我们发现ApoEβ4/ε4 AD患者脑中Aβ寡聚体的水平是ApoEε3/ε3 AD患者脑内Aβ寡聚体水平的2.7倍，与总斑块负荷相匹配，表明apoE4影响A ApoE4寡聚体的代谢。为了验证这一假设，我们检验了载脂蛋白E对Aβ寡聚体形成的影响。使用合成的Aβ和裂解荧光素酶方法监测Aβ寡聚体，我们观察到apoE以异构体依赖的方式增加Aβ寡聚体的水平(E2<；E3<；E4)。这一效应似乎依赖于ApoE的羧基末端结构域。此外，从人脑TBS可溶性部分分离的内源性载脂蛋白E证实了这些结果，它增加了Aβ寡聚体的形成。综上所述，这些数据表明，脂化的载脂蛋白E，特别是载脂蛋白E4，增加了大脑中的Aβ寡聚体。与载脂蛋白βε3/ε3携带者相比，载脂蛋白ε4/ε4携带者脑内A DNA寡聚体水平较高，可能会增加树突棘的丢失，加速记忆损伤，导致AD认知功能早期下降。
Alzheimer’s disease (AD) is the most common progressive neurodegenerative disorder causing dementia. Massive deposition of amyloid β peptide (Aβ) as senile plaques in the brain is the pathological hallmark of AD, but oligomeric, soluble forms of Aβ have been implicated as the synaptotoxic component. The apolipoprotein E epsilon 4 (apoE ε4) allele is known to be a genetic risk factor for developing AD. However it is still unknown how apoE impacts the process of Aβ oligomerization. Here, we found that the level of Aβ oligomers in APOEε4/ε4 AD patient brains is 2.7 times higher than those in APOEε3/ε3 AD patient brains, matched for total plaque burden, suggesting that apoE4 impacts the metabolism of Aβ oligomers. To test this hypothesis, we examined apoE’s effect on Aβ oligomer formation. Using both synthetic Aβ and a split-luciferase method for monitoring Aβ oligomers, we observed that apoE increased the level of Aβ oligomers in an isoform dependent manner (E2 < E3 < E4). This effect appears to be dependent on the ApoE carboxy-terminal domain. Moreover, these results were confirmed using endogenous apoE isolated from the TBS-soluble fraction of human brain, which increased the formation of Aβ oligomers. Taken together, these data show that lipidated apoE, especially apoE4, increases Aβ oligomers in the brain. Higher levels of Aβ oligomers in the brains of APOEε4/ε4 carriers compared to APOEε3/ε3 carriers may increase the loss of dendritic spines and accelerate memory impairments, leading to earlier cognitive decline in AD.