Aβ oligomers trigger necroptosis-mediated neurodegeneration via microglia activation in Alzheimer's disease.
Aβ oligomers trigger necroptosis-mediated neurodegeneration via microglia activation in Alzheimer's disease.
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DOI：
10.1186/s40478-022-01332-9
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发表时间：
2022-03-09
影响因子：
7.1
通讯作者：
Court FA
中科院分区：
文献类型：
--
作者：
Salvadores N;Moreno-Gonzalez I;Gamez N;Quiroz G;Vegas-Gomez L;Escandón M;Jimenez S;Vitorica J;Gutierrez A;Soto C;Court FA
阿尔茨海默病（AD）是一种主要的成人发病的神经退行性疾病，目前尚无有效的治疗方法。令人信服的报告指出淀粉样蛋白-β（Aβ）是触发AD的主要病原体。虽然有大量证据表明Aβ和小胶质细胞之间的有害串扰有助于AD中的神经炎症，但导致神经元死亡的确切机制仍然未知。使用死后人类AD脑组织，我们表明Aβ病理与坏死性凋亡效应子pMLKL相关。此外，我们发现Aβ寡聚体（Aβo）的负荷与坏死性凋亡激活的关键标志物的表达相关。此外，通过药理学或遗传学手段抑制坏死性凋亡，可减少小鼠中由Aβo引发的神经变性和记忆障碍。由于小胶质细胞活化正在成为AD发病机制的中心驱动因素，因此我们随后测试了小胶质细胞对神经元中Aβ o介导的坏死性凋亡活化机制的贡献。使用体外模型，我们发现Aβ o刺激的小胶质细胞的条件培养基通过激活TNF-α信号转导引起神经元的坏死性凋亡，从而引发广泛的神经变性。值得注意的是，坏死性凋亡抑制提供了显著的神经元保护。总之，这些发现表明AD中Aβ o介导的小胶质细胞刺激有助于神经元中的坏死性凋亡激活和神经变性。由于坏死性凋亡是一种可药物治疗的退行性机制，我们的研究结果可能对预防AD的进展具有重要的治疗意义。在线版本包含补充材料，可通过10.1186/s40478-022-01332-9获得。
Alzheimer’s disease (AD) is a major adult-onset neurodegenerative condition with no available treatment. Compelling reports point amyloid-β (Aβ) as the main etiologic agent that triggers AD. Although there is extensive evidence of detrimental crosstalk between Aβ and microglia that contributes to neuroinflammation in AD, the exact mechanism leading to neuron death remains unknown. Using postmortem human AD brain tissue, we show that Aβ pathology is associated with the necroptosis effector pMLKL. Moreover, we found that the burden of Aβ oligomers (Aβo) correlates with the expression of key markers of necroptosis activation. Additionally, inhibition of necroptosis by pharmacological or genetic means, reduce neurodegeneration and memory impairment triggered by Aβo in mice. Since microglial activation is emerging as a central driver for AD pathogenesis, we then tested the contribution of microglia to the mechanism of Aβo-mediated necroptosis activation in neurons. Using an in vitro model, we show that conditioned medium from Aβo-stimulated microglia elicited necroptosis in neurons through activation of TNF-α signaling, triggering extensive neurodegeneration. Notably, necroptosis inhibition provided significant neuronal protection. Together, these findings suggest that Aβo-mediated microglia stimulation in AD contributes to necroptosis activation in neurons and neurodegeneration. As necroptosis is a druggable degenerative mechanism, our findings might have important therapeutic implications to prevent the progression of AD. The online version contains supplementary material available at 10.1186/s40478-022-01332-9.
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DOI：
10.1056/nejmoa1211851
发表时间：
2013-01-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
通讯作者：
Alzheimer Genetic Analysis Group
CD36介导了对β-淀粉样蛋白的先天宿主反应。
影响因子：
15.3
作者：
El Khoury, JB;Moore, KJ;Means, TK;Leung, J;Terada, K;Toft, M;Freeman, MW;Luster, AD
通讯作者：
Luster, AD
DOI：
10.3233/jad-179941
发表时间：
2018
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Cline EN;Bicca MA;Viola KL;Klein WL
通讯作者：
Klein WL
影响因子：
4.8
作者：
Kaiser, William J.;Sridharan, Haripriya;Mocarski, Edward S.
通讯作者：
Mocarski, Edward S.
影响因子：
14
作者：
通讯作者：
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