Lipid-accumulated Reactive Astrocytes Promote Disease Progression in Epilepsy

Zhang-Peng Chen,Suji Wang,Xiansen Zhao,Wen Fang,Zhengge Wang, Haojie Ye, Meng-Ju Wang, Ling Ke,Tengfei Huang,Pin Lv,Xiaohong Jiang,Qipeng Zhang,Liang Li,Shu-Tao Xie,Jing-Ning Zhu,Chunhua Hang,Dijun Chen,Xiangyu Liu,Chao Yan

Nature Neuroscience（2023）

State Key Laboratory of Pharmaceutical Biotechnology | Department of Radiology | Department of Neurosurgery | Epilepsy Center

Cited 26|Views13

Abstract

Reactive astrocytes play an important role in neurological diseases, but their molecular and functional phenotypes in epilepsy are unclear. Here, we show that in patients with temporal lobe epilepsy (TLE) and mouse models of epilepsy, excessive lipid accumulation in astrocytes leads to the formation of lipid-accumulated reactive astrocytes (LARAs), a new reactive astrocyte subtype characterized by elevated APOE expression. Genetic knockout of APOE inhibited LARA formation and seizure activities in epileptic mice. Single-nucleus RNA sequencing in TLE patients confirmed the existence of a LARA subpopulation with a distinct molecular signature. Functional studies in epilepsy mouse models and human brain slices showed that LARAs promote neuronal hyperactivity and disease progression. Targeting LARAs by intervention with lipid transport and metabolism could thus provide new therapeutic options for drug-resistant TLE.

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Key words

Astrocyte,Epilepsy,Biomedicine,general,Neurosciences,Behavioral Sciences,Biological Techniques,Neurobiology,Animal Genetics and Genomics

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