Molecular Pathways and Diagnosis in Spatially Resolved Alzheimer’s Hippocampal Atlas
Alzheimer’s Disease (AD) is the most common form of dementia, characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain, leading to the progressive deterioration of brain function. Although Aβ plaques and NFTs have long been considered hallmarks of AD pathology, therapeutic strategies targeting these pathological proteins have shown limited effectiveness and are often accompanied by severe side effects. Therefore, a deeper understanding of the pathological mechanisms of AD at the molecular and cellular levels is crucial for developing disease-modifying therapies.
The hippocampus is a brain region closely associated with memory, navigation, and cognition, and it is particularly vulnerable to damage in the early stages of AD. However, research on the molecular and cellular changes in the hippocampus in AD has primarily relied on mouse models, and a systematic spatial transcriptomic atlas of the human hippocampus has not yet been established. To address this, this study aims to construct a spatial transcriptomic atlas of the human hippocampus in AD using spatial transcriptomics and single-nucleus RNA sequencing (snRNA-seq) technologies, revealing AD-related cellular and functional changes, the Aβ microenvironment, and spatial pathological features.
Source of the Paper
This paper was co-authored by Pan Wang, Lei Han, Lifang Wang, and other researchers from institutions such as Zhejiang University, BGI Research, and Tencent AI Lab. It was published in the journal Neuron on July 9, 2025, under the title “Molecular Pathways and Diagnosis in Spatially Resolved Alzheimer’s Hippocampal Atlas.”
Research Process and Results
1. Sample Collection and Experimental Design
The research team obtained 16 postmortem hippocampus samples from the National Human Brain Bank for Health and Disease in China, including 8 samples from moderate to severe AD patients (Braak III-V stage, abundant Aβ plaques) and 8 age- and sex-matched controls without dementia or hippocampal pathology. All samples underwent rigorous neuropathological diagnosis to ensure they met the study criteria.
2. Spatial Transcriptomics and Single-nucleus RNA Sequencing
The research team used spatially enhanced resolution omics sequencing (Stereo-seq) and single-nucleus RNA sequencing technologies to analyze the spatial transcriptome of hippocampus samples. Through Stereo-seq, the researchers were able to map gene expression in different subregions of the hippocampus at single-cell resolution. Meanwhile, snRNA-seq was used to analyze gene expression and cellular composition changes in hippocampal cells.
3. Data Integration and Analysis
By integrating Stereo-seq and snRNA-seq data, the research team constructed a spatial transcriptomic atlas of the hippocampus in AD and control groups and identified differentially expressed genes (DEGs) associated with AD. The results showed widespread changes in gene expression in the AD hippocampus, particularly in metabolism, oxidative phosphorylation, and immune regulation.
4. Cellular Distribution and Functional Changes
The study found significant changes in the distribution and function of microglia and astrocytes in the AD hippocampus. Microglia and astrocytes exhibited a “core-shell” structure around Aβ plaques, with microglia primarily clustered at the plaque core and astrocytes distributed at the periphery. Additionally, the study revealed a reduction in the number of neurons in the AD hippocampus, especially in the CA1 region, while neurons in the CA4 region showed strong resistance to AD.
5. Diagnostic Potential of Plasma Extracellular Vesicles (EVs)
The research team further analyzed brain-derived extracellular vesicles in the plasma of AD patients and found a significant reduction in EVs carrying cholecystokinin (CCK) and peripheral myelin protein 2 (PMP2). These EVs have potential applications in AD diagnosis and can effectively distinguish AD patients from healthy controls.
Conclusions and Significance
This study constructed a spatial transcriptomic atlas of the human hippocampus in AD, revealing AD-related cellular and molecular changes, particularly the microenvironment and cellular distribution patterns around Aβ plaques. The study also identified the significant potential of plasma EVs carrying CCK and PMP2 in AD diagnosis, providing new biomarkers for early AD detection.
Research Highlights
- Single-cell resolution spatial transcriptomic atlas: This study is the first to map the spatial transcriptome of the human hippocampus in AD at single-cell resolution, revealing AD-related cellular and molecular changes.
- Microenvironment analysis of Aβ plaques: The study found specific distribution patterns of microglia and astrocytes around Aβ plaques, providing new insights into the pathological mechanisms of AD.
- Diagnostic potential of plasma EVs: The study is the first to identify the diagnostic value of plasma EVs carrying CCK and PMP2, offering a new tool for early AD diagnosis.
Other Valuable Information
The research team also developed a rapid detection method based on nanoflow cytometry, which can efficiently detect EVs in plasma, providing convenient technical support for the clinical diagnosis of AD. Additionally, the research team created an interactive website (https://db.cngb.org/stomics/hhsta/) for researchers to download and analyze the study data.
Summary
By constructing a spatial transcriptomic atlas of the human hippocampus in AD, this study deeply revealed AD-related cellular and molecular changes, providing important insights for understanding the pathological mechanisms of AD and developing new diagnostic methods. The findings not only have significant scientific value but also offer new ideas and tools for the early diagnosis and treatment of AD.