ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy.
ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy.
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DOI：
10.1038/nature24016
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发表时间：
2017-09-28
期刊：
影响因子：
64.8
通讯作者：
Holtzman DM
中科院分区：
文献类型：
--
作者：
Shi Y;Yamada K;Liddelow SA;Smith ST;Zhao L;Luo W;Tsai RM;Spina S;Grinberg LT;Rojas JC;Gallardo G;Wang K;Roh J;Robinson G;Finn MB;Jiang H;Sullivan PM;Baufeld C;Wood MW;Sutphen C;McCue L;Xiong C;Del-Aguila JL;Morris JC;Cruchaga C;Alzheimer’s Disease Neuroimaging Initiative;Fagan AM;Miller BL;Boxer AL;Seeley WW;Butovsky O;Barres BA;Paul SM;Holtzman DM
载脂蛋白E4是晚发性阿尔茨海默病(AD)最强的遗传风险因素。与其他载脂蛋白E亚型相比，载脂蛋白E4可增加脑淀粉样蛋白-β(Aβ)的病理改变。然而，APOE是否独立地影响tau病理，AD和其他tau病的另一种主要蛋白质病，或tau介导的神经变性，尚不清楚。通过在人类ApoE基因敲除(KI)或ApoE基因敲除(KO)背景下建立P301S tau转基因小鼠，我们发现P301S/E4小鼠在3个月龄时比P301S/E2、P301S/E3和P301S/EKO小鼠具有显著更高的脑组织tau水平和更大程度的躯体树突状细胞tau重新分布。到9个月龄时，不同载脂蛋白E基因的P301S小鼠表现出不同的p-tau染色模式。与P301S/E2和P301S/E3小鼠相比，P301S/E4小鼠发生明显更多的脑萎缩和神经炎症，而P301S/EKO小鼠在很大程度上免受这些变化的影响。在体外，表达E4的小胶质细胞在脂多糖处理后表现出更高的先天免疫反应性。与神经元/E2和神经元/E3共培养相比，表达P301S tau的神经元和表达E4的混合胶质细胞可显著增加肿瘤坏死因子α的分泌，并显著降低神经元的存活率。与EKO胶质细胞共培养的神经元存活率最高，分泌肿瘤坏死因子α的水平最低。与没有ApoE相比，重组ApoE(E2、E3、E4)处理P301S神经元也会导致一些神经元的损伤和死亡，而ApoE4则加剧了这种作用。在散发性原发肌萎缩症患者中，ε4等位基因的存在与更严重的区域性神经变性有关。在Aβ病理阳性的症状性AD患者中，通常有tau病理，ε4携带者表现出更高的疾病进展速度。我们的结果表明，载脂蛋白E影响tau的发病机制、神经炎症和tau介导的神经变性，而不依赖于Aβ的病理。载脂蛋白E4发挥“有毒”的功能，而缺乏载脂蛋白E则是保护性的。
APOE4 is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). ApoE4 increases brain amyloid-β (Aβ) pathology relative to other ApoE isoforms. However, whether APOE independently influences tau pathology, the other major proteinopathy of AD and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knockin (KI) or ApoE knockout (KO) background, we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by 3 months of age compared to P301S/E2, P301S/E3 and P301S/EKO mice. By 9 months of age, P301S mice with different ApoE genotypes display distinct p-tau staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity following LPS treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of TNFα secretion and markedly reduced neuronal viability compared to neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNFα. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared to the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In Aβ-pathology positive individuals with symptomatic AD who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independent of Aβ pathology. ApoE4 exerts a “toxic” gain of function whereas the absence of ApoE is protective.
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DOI：
10.1523/jneurosci.6221-11.2012
发表时间：
2012-05-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Zamanian JL;Xu L;Foo LC;Nouri N;Zhou L;Giffard RG;Barres BA
通讯作者：
Barres BA
影响因子：
11.2
作者：
Butovsky, Oleg;Jedrychowski, Mark P.;Cialic, Ron;Krasemann, Susanne;Murugaiyan, Gopal;Fanek, Zain;Greco, David J.;Wu, Pauline M.;Doykan, Camille E.;Kiner, Olga;Lawson, Robert J.;Frosch, Matthew P.;Pochet, Nathalie;El Fatimy, Rachid;Krichevsky, Anna M.;Gygi, Steven P.;Lassmann, Hans;Berry, James;Cudkowicz, Merit E.;Weiner, Howard L.
通讯作者：
Weiner, Howard L.
影响因子：
12.7
作者：
Grinberg LT;Wang X;Wang C;Sohn PD;Theofilas P;Sidhu M;Arevalo JB;Heinsen H;Huang EJ;Rosen H;Miller BL;Gan L;Seeley WW
通讯作者：
Seeley WW
DOI：
10.1073/pnas.90.5.1977
发表时间：
1993-03-01
影响因子：
11.1
作者：
STRITTMATTER, WJ;SAUNDERS, AM;ROSES, AD
通讯作者：
ROSES, AD
DOI：
10.1073/pnas.0812697106
发表时间：
2009-02-10
影响因子：
11.1
作者：
Agosta, Federica;Vossel, Keith A.;Gorno-Tempini, Maria Luisa
通讯作者：
Gorno-Tempini, Maria Luisa