Nature genetics · 2024
Spatial and single-nucleus transcriptomic analysis of genetic and sporadic forms of Alzheimer's disease.
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Miyoshi Emily, Morabito Samuel, Henningfield Caden M, Das Sudeshna, Rahimzadeh Negin, Shabestari Sepideh Kiani, Michael Neethu, Emerson Nora, Reese Fairlie, Shi Zechuan, Cao Zhenkun, Srinivasan Shushrruth Sai, Scarfone Vanessa M, Arreola Miguel A, Lu Jackie, Wright Sierra, Silva Justine, Leavy Kelsey, Lott Ira T, Doran Eric, Yong William H, Shahin Saba, Perez-Rosendahl Mari, Alzheimer’s Biomarkers Consortium–Down Syndrome (ABC–DS), Head Elizabeth, Green Kim N, Swarup Vivek
Аннотация
The pathogenesis of Alzheimer's disease (AD) depends on environmental and heritable factors, with its molecular etiology still unclear. Here we present a spatial transcriptomic (ST) and single-nucleus transcriptomic survey of late-onset sporadic AD and AD in Down syndrome (DSAD). Studying DSAD provides an opportunity to enhance our understanding of the AD transcriptome, potentially bridging the gap between genetic mouse models and sporadic AD. We identified transcriptomic changes that may underlie cortical layer-preferential pathology accumulation. Spatial co-expression network analyses revealed transient and regionally restricted disease processes, including a glial inflammatory program dysregulated in upper cortical layers and implicated in AD genetic risk and amyloid-associated processes. Cell-cell communication analysis further contextualized this gene program in dysregulated signaling networks. Finally, we generated ST data from an amyloid AD mouse model to identify cross-species amyloid-proximal transcriptomic changes with conformational context.