Flury Anna, Aljayousi Leen, Park Hye-Jin, Khakpour Mohammadparsa, Mechler Jack, Aziz Siaresh, McGrath Jackson D, Deme Pragney, Sandberg Colby, González Ibáñez Fernando, Braniff Olivia, Ngo Thi, Smith Simira, Velez Matthew, Ramirez Denice Moran, Avnon-Klein Dvir, Murray John W, Liu Jia, Parent Martin, Mingote Susana, Haughey Norman J, Werneburg Sebastian, Tremblay Marie-Ève, Ayata Pinar
Neuroscience Initiative, Advanced Science Research Center, The City University of New York (CUNY) Graduate Center, New York, NY 10031, USA; Graduate Program in Biology, CUNY Graduate Center, New York, NY 10016, USA.
Neuroscience Initiative, Advanced Science Research Center, The City University of New York (CUNY) Graduate Center, New York, NY 10031, USA.
Neuron. 2025 Feb 19;113(4):554-571.e14. doi: 10.1016/j.neuron.2024.11.018. Epub 2024 Dec 23.
The brain's primary immune cells, microglia, are a leading causal cell type in Alzheimer's disease (AD). Yet, the mechanisms by which microglia can drive neurodegeneration remain unresolved. Here, we discover that a conserved stress signaling pathway, the integrated stress response (ISR), characterizes a microglia subset with neurodegenerative outcomes. Autonomous activation of ISR in microglia is sufficient to induce early features of the ultrastructurally distinct "dark microglia" linked to pathological synapse loss. In AD models, microglial ISR activation exacerbates neurodegenerative pathologies and synapse loss while its inhibition ameliorates them. Mechanistically, we present evidence that ISR activation promotes the secretion of toxic lipids by microglia, impairing neuron homeostasis and survival in vitro. Accordingly, pharmacological inhibition of ISR or lipid synthesis mitigates synapse loss in AD models. Our results demonstrate that microglial ISR activation represents a neurodegenerative phenotype, which may be sustained, at least in part, by the secretion of toxic lipids.
大脑的主要免疫细胞——小胶质细胞，是阿尔茨海默病（AD）的主要致病细胞类型。然而，小胶质细胞驱动神经退行性变的机制仍未得到解决。在这里，我们发现一种保守的应激信号通路——综合应激反应（ISR），是具有神经退行性变结果的小胶质细胞亚群的特征。小胶质细胞中ISR的自主激活足以诱导与病理性突触丧失相关的超微结构上不同的“暗小胶质细胞”的早期特征。在AD模型中，小胶质细胞ISR激活会加剧神经退行性病变和突触丧失，而抑制它则会改善这些情况。从机制上讲，我们提供的证据表明，ISR激活会促进小胶质细胞分泌有毒脂质，损害体外神经元的内环境稳态和存活。因此，对ISR或脂质合成的药理学抑制可减轻AD模型中的突触丧失。我们的结果表明，小胶质细胞ISR激活代表一种神经退行性表型，这可能至少部分地由有毒脂质的分泌所维持。
