Integrative in situ mapping of single-cell transcriptional states and tissue histopathology in an Alzheimer disease model

Amyloid-β plaques and neurofibrillary tau tangles are the neuropathologic hallmarks of Alzheimer’s disease (AD), but the spatiotemporal cellular responses and molecular mechanisms underlying AD pathophysiology remain poorly understood. Here we introduce STARmap PLUS to simultaneously map single-cell transcriptional states and disease marker proteins in brain tissues of AD mouse models at a voxel size of 95  95  350 nm. This high-resolution spatial transcriptomics map revealed a core-shell structure where disease-associated microglia (DAM) closely contact amyloid-β plaques, whereas disease-associated astrocyte-like cells (DAA-like) and oligodendrocyte precursor cells (OPC) are enriched in the outer shells surrounding the plaque-DAM complex. Hyperphosphorylated tau emerged mainly in excitatory neurons in the CA1 region accompanied by infiltration of oligodendrocyte subtypes into the axon bundles of hippocampal alveus. The integrative STARmap PLUS method bridges single-cell gene expression profiles with tissue histopathology at subcellular resolution, providing an unprecedented roadmap to pinpoint the molecular and cellular mechanisms of AD pathology and neurodegeneration.β淀粉样斑块（Amyloid-β plaques）与神经原纤维tau缠结（neurofibrillary tau tangles）是阿尔茨海默病（AD，Alzheimer’s disease）的神经病理标志性特征，但AD病理生理过程背后的时空细胞应答与分子机制仍尚未被充分阐明。本研究引入STARmap PLUS技术，以95×95×350纳米的体素分辨率，同时绘制AD小鼠模型脑组织中的单细胞转录状态与疾病标志物蛋白图谱。该高分辨率空间转录组图谱揭示了一种核壳结构：疾病相关小胶质细胞（disease-associated microglia, DAM）与β淀粉样斑块紧密毗邻；而疾病相关星形胶质样细胞（disease-associated astrocyte-like cells, DAA-like）与少突胶质前体细胞（oligodendrocyte precursor cells, OPC）则富集于斑块-DAM复合物外围的壳层区域。过度磷酸化tau蛋白主要表达于CA1区的兴奋性神经元中，同时伴有少突胶质细胞亚型浸润至海马槽（hippocampal alveus）的轴突束内。该整合式STARmap PLUS技术将单细胞基因表达谱与亚细胞分辨率下的组织病理特征相结合，为精准解析AD病理与神经退行性变的分子及细胞机制提供了前所未有的研究蓝图。