Lipid-accumulated reactive astrocytes promote disease progression in epilepsy PMID: 36941428

ADC Targets in Oncology

2026-04-10

Lipid-accumulated reactive astrocytes promote disease progression in epilepsy

Nat Neurosci. 2023 Mar 20. doi: 10.1038/s41593-023-01288-6.

Zhang-Peng Chen ^# ¹ ² ³ , Suji Wang ^# ⁴ , Xiansen Zhao ^# ⁴ , Wen Fang ^# ⁴ , Zhengge Wang ⁵ ⁶ , Haojie Ye ⁴ , Meng-Ju Wang ⁴ , Ling Ke ⁴ , Tengfei Huang ⁴ , Pin Lv ⁵ , Xiaohong Jiang ⁴ ⁷ , Qipeng Zhang ⁴ ⁸ , Liang Li ⁴ ⁸ , Shu-Tao Xie ⁴ ⁸ , Jing-Ning Zhu ⁴ ⁸ , Chunhua Hang ⁹ , Dijun Chen ¹⁰ , Xiangyu Liu ¹¹ ¹² , Chao Yan ¹³ ¹⁴ ¹⁵ ¹⁶ ¹⁷ ¹⁸

Affiliations

1. State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China. [email protected].
2. Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing, China. [email protected].
3. Institute of Artificial Intelligence Biomedicine, Nanjing University, Nanjing, China. [email protected].
4. State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
5. Department of Radiology, the Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
6. Epilepsy Center, the Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
7. Institute of Artificial Intelligence Biomedicine, Nanjing University, Nanjing, China.
8. Institute for Brain Sciences, Nanjing University, Nanjing, China.
9. Department of Neurosurgery, the Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
10. State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China. [email protected].
11. Epilepsy Center, the Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China. [email protected].
12. Department of Neurosurgery, the Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China. [email protected].
13. State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China. [email protected].
14. Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing, China. [email protected].
15. Institute of Artificial Intelligence Biomedicine, Nanjing University, Nanjing, China. [email protected].
16. Epilepsy Center, the Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China. [email protected].
17. Institute for Brain Sciences, Nanjing University, Nanjing, China. [email protected].
18. Engineering Research Center of Protein and Peptide Medicine, Ministry of Education, Nanjing, China. [email protected].
# Contributed equally.

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.