Spatiotemporal characterization of disease-associated neurons in the entorhinal cortex-hippocampal circuit during Alzheimer's disease progression

Yuting Ma; Juan Zhang; Hankui Liu; Dingfeng Li; Sicheng Guo; Jialuo Han; Lei Wang; Shaojun Yu; Xi Su; Yongchang Gao; Xiumei Lin; Ciren Asan; Yushan Peng; Guibo Li; Hui Jiang; Wei Wang; Huanming Yang; Jian Wang; Shida Zhu; Lijian Zhao; Jianguo Zhang; Qiang Liu

doi:10.1093/procel/pwaf042

Protein Cell ›› 2025, Vol. 16 ›› Issue (9) : 799 -814. DOI: 10.1093/procel/pwaf042

RESEARCH ARTICLE

Spatiotemporal characterization of disease-associated neurons in the entorhinal cortex-hippocampal circuit during Alzheimer's disease progression

Yuting Ma ¹^,²^,³
, Juan Zhang ⁴^,⁵^,⁶^,⁷
, Hankui Liu ¹^,³^,⁸
, Dingfeng Li ⁴^,⁵
, Sicheng Guo ¹^,²^,³
, Jialuo Han ⁴^,⁵
, Lei Wang ⁹
, Shaojun Yu ⁹
, Xi Su ¹^,³
, Yongchang Gao ¹^,¹⁰
, Xiumei Lin ⁹
, Ciren Asan ¹^,³
, Yushan Peng ⁹
, Guibo Li ⁹
, Hui Jiang ¹^,⁹
, Wei Wang ¹
, Huanming Yang ¹¹
, Jian Wang ¹¹
, Shida Zhu ¹
, Lijian Zhao ¹^,³^,⁸^,¹²^,¹³
, Jianguo Zhang ¹^,³^,⁸^,¹³
, Qiang Liu ⁴^,⁵^,⁶^,⁷

Author information +

¹. BGI Genomics, Shenzhen 518083, China

². College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China

³. Hebei Industrial Technology Research Institute of Genomics in Maternal & Child Health, Clin Lab, BGI Genomics, Shijiazhuang 050000, China

⁴. Hefei National Research Center for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China

⁵. Anhui Province Key Laboratory of Biomedical Aging Research, University of Science and Technology of China, Hefei 230027, China

⁶. CAS Key Laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei 230026, China

⁷. Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230071, China

⁸. Hebei Provincial Technology Innovation Center for Precision Medicine Diagnosis and Quality Control, Shijiazhuang 050000, China

⁹. BGI Research, Shenzhen 518083, China

¹⁰. School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing 100049, China

¹¹. BGI, Shenzhen 518083, China

¹². Medical Technology College, Hebei Medical University, Shijiazhuang 050000, China

¹³. School of Public Health, Hebei Medical University, Shijiazhuang 050000, China

zhaolijian@bgi.com (L. Zhao)

zhangjg@genomics.com (J. Zhang)

liuq2012@ustc.edu.cn (Q. Liu)

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Abstract

The entorhinal cortex (EC)-hippocampal (HPC) circuit is particularly vulnerable to Alzheimer's disease (AD) pathology, yet the underlying molecular mechanisms remain unclear. By employing the high-depth sequencing strategy Smart-seq2, we tracked gene expression changes across various neuron types within this circuit at different stages of AD pathology. We observed a decrease in the extent of gene expression changes in AD versus wild-type (WT) mice as the disease advanced. Functionally, we demonstrate that both mitochondrial and ribosomal pathways were increasingly activated, while neuronal pathways were inhibited with AD progression. Our findings indicate that the reduction of EC-stellate cells disrupts Meg3-mediated energy metabolism, contributing to energy dysfunction in AD. Additionally, we identified GFAP-positive neurons as a distinct population of disease-associated neurons, exhibiting a loss of neuronal-like characteristics, alongside the emergence of glia- and stem-like features. The number of GFAP-positive neurons increased with AD progression, a trend consistently observed in both AD model mice and AD patients. In summary, this study identifies and characterizes GFAP-positive neurons as a novel subtype of disease-associated neurons in AD pathology, providing insights into their potential role in disease progression.

Keywords

Alzheimer's disease / EC-HPC neuronal circuit / Smart-seq2 / GFAP / energy metabolism

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Yuting Ma, Juan Zhang, Hankui Liu, Dingfeng Li, Sicheng Guo, Jialuo Han, Lei Wang, Shaojun Yu, Xi Su, Yongchang Gao, Xiumei Lin, Ciren Asan, Yushan Peng, Guibo Li, Hui Jiang, Wei Wang, Huanming Yang, Jian Wang, Shida Zhu, Lijian Zhao, Jianguo Zhang, Qiang Liu. Spatiotemporal characterization of disease-associated neurons in the entorhinal cortex-hippocampal circuit during Alzheimer's disease progression. Protein Cell, 2025, 16(9): 799-814 DOI:10.1093/procel/pwaf042

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