Molecular pathways and diagnosis in spatially resolved Alzheimer's hippocampal atlas

Pan Wang¹, Lei Han², Lifang Wang², Quyuan Tao³, Zhen Guo⁴, Ting Luo², Youzhe He³, Zhi Xu⁴, Jiayi Yu⁴, Yuyang Liu³, Zihan Wu⁵, Bin Xu⁶, Bufan Jin³, Yanrong Wei³, Ying Yang⁶, Mengnan Cheng³, Yujia Jiang⁷, Chen Tian⁶, Huiwen Zheng³, Zhongqin Fan⁶, Peiran Jiang⁸, Yue Gao⁷, Juanli Wu⁸, Shengpeng Wang⁷, Bing Sun⁸, Zheng Fang⁸, Junjie Lei³, Benyan Luo⁹, Huiying Wen⁷, Guoping Peng⁹, Yuanchun Tang⁷, Tao Yang¹⁰, Jing Chen¹⁰, Zhenkun Zhuang⁷, Xinhui Su¹¹, Catherine Pan⁴, Keqing Zhu¹², Yi Shen¹³, Shiping Liu⁷, Aimin Bao¹⁴, Jianhua Yao⁵, Jian Wang¹⁵, Xun Xu¹⁶, Xiao-Ming Li¹⁴, Longqi Liu¹⁷, Shumin Duan¹⁸, Jing Zhang¹⁹

Affiliations

¹ Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310002, China; National Human Brain Bank for Health and Disease, Zhejiang University, Hangzhou, Zhejiang 310002, China; School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang 310002, China.
² BGI Research, Hangzhou 310030, China; BGI Research, Shenzhen 518083, China.
³ BGI Research, Hangzhou 310030, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
⁴ Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310002, China; School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang 310002, China.
⁵ Tencent AI Lab, Shenzhen 518057, China.
⁶ Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310002, China.
⁷ BGI Research, Hangzhou 310030, China.
⁸ National Human Brain Bank for Health and Disease, Zhejiang University, Hangzhou, Zhejiang 310002, China.
⁹ Department of Neurology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
¹⁰ China National GeneBank, BGI Research, Shenzhen 518120, China; Guangdong Provincial Genomics Data Center, BGI Research, Shenzhen 518120, China.
¹¹ PET Center, Department of Nuclear Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China.
¹² National Human Brain Bank for Health and Disease, Zhejiang University, Hangzhou, Zhejiang 310002, China; Department of Pathology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
¹³ Department of Neurobiology and Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310002, China.
¹⁴ NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310002, China; Department of Neurobiology and Department of Neurology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China.
¹⁵ BGI Research, Shenzhen 518083, China.
¹⁶ BGI Research, Hangzhou 310030, China; BGI Research, Shenzhen 518083, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
¹⁷ BGI Research, Hangzhou 310030, China; BGI Research, Shenzhen 518083, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: liulongqi@genomics.cn.
¹⁸ Department of Neurobiology and Department of Neurology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Liangzhu Laboratory, Zhejiang University Medical Center, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, Zhejiang University, Hangzhou 310002, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310002, China. Electronic address: duanshumin@zju.edu.cn.
¹⁹ Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310002, China; National Human Brain Bank for Health and Disease, Zhejiang University, Hangzhou, Zhejiang 310002, China; School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang 310002, China. Electronic address: jzhang1989@zju.edu.cn.

PMID: 40168986
DOI: 10.1016/j.neuron.2025.03.002

Molecular pathways and diagnosis in spatially resolved Alzheimer's hippocampal atlas

Pan Wang et al. Neuron. 2025.

. 2025 Jul 9;113(13):2123-2140.e9.

doi: 10.1016/j.neuron.2025.03.002. Epub 2025 Mar 31.

Authors

Affiliations

¹ Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310002, China; National Human Brain Bank for Health and Disease, Zhejiang University, Hangzhou, Zhejiang 310002, China; School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang 310002, China.
² BGI Research, Hangzhou 310030, China; BGI Research, Shenzhen 518083, China.
³ BGI Research, Hangzhou 310030, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
⁴ Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310002, China; School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang 310002, China.
⁵ Tencent AI Lab, Shenzhen 518057, China.
⁶ Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310002, China.
⁷ BGI Research, Hangzhou 310030, China.
⁸ National Human Brain Bank for Health and Disease, Zhejiang University, Hangzhou, Zhejiang 310002, China.
⁹ Department of Neurology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
¹⁰ China National GeneBank, BGI Research, Shenzhen 518120, China; Guangdong Provincial Genomics Data Center, BGI Research, Shenzhen 518120, China.
¹¹ PET Center, Department of Nuclear Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China.
¹² National Human Brain Bank for Health and Disease, Zhejiang University, Hangzhou, Zhejiang 310002, China; Department of Pathology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
¹³ Department of Neurobiology and Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310002, China.
¹⁴ NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310002, China; Department of Neurobiology and Department of Neurology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China.
¹⁵ BGI Research, Shenzhen 518083, China.
¹⁶ BGI Research, Hangzhou 310030, China; BGI Research, Shenzhen 518083, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
¹⁷ BGI Research, Hangzhou 310030, China; BGI Research, Shenzhen 518083, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: liulongqi@genomics.cn.
¹⁸ Department of Neurobiology and Department of Neurology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Liangzhu Laboratory, Zhejiang University Medical Center, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, Zhejiang University, Hangzhou 310002, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310002, China. Electronic address: duanshumin@zju.edu.cn.
¹⁹ Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310002, China; National Human Brain Bank for Health and Disease, Zhejiang University, Hangzhou, Zhejiang 310002, China; School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang 310002, China. Electronic address: jzhang1989@zju.edu.cn.

PMID: 40168986
DOI: 10.1016/j.neuron.2025.03.002

Abstract

We employed Stereo-seq combined with single-nucleus RNA sequencing (snRNA-seq) to investigate the gene expression and cell composition changes in human hippocampus with or without Alzheimer's disease (AD). The transcriptomic map, with single-cell precision, unveiled AD-associated alterations with spatial specificity, which include the following: (1) elevated synapse pruning gene expression in the fimbria of AD, with disrupted microglia-astrocyte communication likely leading to disorganized synaptic structure; (2) a globally increased energy generation in the cornu ammonis (CA) region, with varying degrees across its subregions; (3) a significant reduction in the number of CA1 neurons in AD, while CA4 neurons remained largely unaffected, potentially due to gene alterations in CA4 conferring resilience to AD; and (4) aggravated amyloid-beta (Aβ) plaques in CA1 and stratum lucidum, radiatum, and moleculare (SLRM), and integration of Stereo-seq map with Aβ staining revealed a sequential enrichment of microglia and astrocytes around Aβ plaques. Finally, reduced brain-derived extracellular vesicles carrying cholecystokinin (CCK) and peripheral myelin protein 2 (PMP2) in AD plasma highlighted their diagnostic potential for clinical applications.

Keywords: Alzheimer’s disease; Stereo-seq; biomarker; diagnosis; hippocampus.

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Conflict of interest statement

Declaration of interests Employees of BGI have stock holdings in BGI.

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Molecular pathways and diagnosis in spatially resolved Alzheimer's hippocampal atlas

Affiliations

Molecular pathways and diagnosis in spatially resolved Alzheimer's hippocampal atlas

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous