Spatial and single-nucleus transcriptomic analysis of genetic and sporadic forms of Alzheimer’s disease
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.
Authors
- Saba Shahin (ORCID: https://orcid.org/0000-0002-0576-9383)
- Emily Miyoshi (ORCID: https://orcid.org/0000-0001-8151-0560)
- Vanessa M. Scarfone (ORCID: https://orcid.org/0000-0001-8786-4191)
- Nora Emerson (ORCID: https://orcid.org/0000-0001-7344-4487)
- William H. Yong
- Sudeshna Das
- Miguel A. Arreola (ORCID: https://orcid.org/0000-0002-9787-4059)
- Kelsey Leavy
- Justine Silva (ORCID: https://orcid.org/0009-0001-9524-8505)
- Shushrruth Sai Srinivasan (ORCID: https://orcid.org/0000-0003-0635-9068)
- Mari Perez‐Rosendahl (ORCID: https://orcid.org/0000-0002-8786-1932)
- Jackie Lu
- Zechuan Shi (ORCID: https://orcid.org/0000-0002-2844-5816)
- Samuel Morabito (ORCID: https://orcid.org/0000-0002-7768-4856)
- Vivek Swarup (ORCID: https://orcid.org/0000-0003-3762-2746)
- Caden M. Henningfield (ORCID: https://orcid.org/0000-0002-9062-8672)
- Sepideh Kiani Shabestari (ORCID: https://orcid.org/0000-0002-2840-116X)
- Negin Rahimzadeh (ORCID: https://orcid.org/0000-0002-7797-620X)
- Kim N. Green (ORCID: https://orcid.org/0000-0002-6049-6744)
- Elizabeth Head (ORCID: https://orcid.org/0000-0003-1115-6396)
- Fairlie Reese (ORCID: https://orcid.org/0000-0002-9240-0102)
- Neethu Michael
- Ira T. Lott (ORCID: https://orcid.org/0000-0002-3107-0752)
- Zhenkun Cao (ORCID: https://orcid.org/0009-0005-3968-8994)
- Sierra Wright
- Eric Doran
Institutions
- University of California, Irvine (US)
Publication Details
- Journal
- Nature Genetics
- Published
- 2024-11-22
- DOI
- https://doi.org/10.1038/s41588-024-01961-x
- Citations
- 66
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 15.43