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

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.

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Publication Details

Journal
Protein & Cell
Published
2025-05-14
DOI
https://doi.org/10.1093/procel/pwaf042
Citations
3
Primary Topic
Memory and Neural Mechanisms
Type
article
Field-Weighted Citation Impact
4.29

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article

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

Shida Zhu, Yuting Ma, Dingfeng Li, Huanming Yang et al.
3 citations
Protein & Cell
Memory and Neural Mechanisms
4.29
article

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

Shida Zhu, Yuting Ma, Dingfeng Li, Huanming Yang, Shaojun Yu, Hankui Liu, Jialuo Han, Xi Su, Yongchang Gao, Jian Wang, Juan Zhang, Wei Wang, Qiang Liu, Lei Wang, Jianguo Zhang, Xiumei Lin, Sicheng Guo, Yushan Peng, Lijian Zhao
article en
3 citations

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.

Protein & Cell
BGI Group (China) (CN), Hebei Medical University (CN), University of Science and Technology of China (CN), ITRI International (US), Anhui University (CN), Beijing Academy of Artificial Intelligence (CN), Hefei National Center for Physical Sciences at Nanoscale (CN), Botswana Geoscience Institute (BW), Industrial Technology Research Institute (TW), Hebei Provincial Center for Disease Control and Prevention (CN), Hebei Provincial Department of Science and Technology (CN), University of Chinese Academy of Sciences (CN), BGI Genomics, BGI Research (CN), Huazhong University of Science and Technology (CN)
National Natural Science Foundation of China, Chinese Academy of Sciences, University of Science and Technology of China
Openalex Percentile: Top 6%
Memory and Neural Mechanisms
4.29
DOIOpen Access PDFOpenAlex
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