Spatial and single-nucleus transcriptomic analysis of genetic and sporadic forms of Alzheimer's disease

Emily Miyoshi; Samuel Morabito; Caden M Henningfield; Sudeshna Das; Negin Rahimzadeh; Sepideh Kiani Shabestari; Neethu Michael; Nora Emerson; Fairlie Reese; Zechuan Shi; Zhenkun Cao; Shushrruth Sai Srinivasan; Vanessa M Scarfone; Miguel A Arreola; Jackie Lu; Sierra Wright; Justine Silva; Kelsey Leavy; Ira T Lott; Eric Doran; William H Yong; Saba Shahin; Mari Perez-Rosendahl; Alzheimer’s Biomarkers Consortium–Down Syndrome (ABC–DS); Elizabeth Head; Kim N Green; Vivek Swarup

doi:10.1038/s41588-024-01961-x

Spatial and single-nucleus transcriptomic analysis of genetic and sporadic forms of Alzheimer's disease

Nat Genet. 2024 Dec;56(12):2704-2717. doi: 10.1038/s41588-024-01961-x. Epub 2024 Nov 22.

Authors

Emily Miyoshi^#^{1

2}, Samuel Morabito^#^{2

3

4}, Caden M Henningfield^{1

2}, Sudeshna Das^{1

2}, Negin Rahimzadeh^{2

3

4}, Sepideh Kiani Shabestari^{1

5}, Neethu Michael^{1

2}, Nora Emerson^{1

2}, Fairlie Reese^{4

6}, Zechuan Shi^{1

2}, Zhenkun Cao¹, Shushrruth Sai Srinivasan^{2

3

4

7}, Vanessa M Scarfone⁵, Miguel A Arreola^{1

2}, Jackie Lu¹, Sierra Wright², Justine Silva^{1

2}, Kelsey Leavy², Ira T Lott^{2

8}, Eric Doran⁸, William H Yong^{2

9}, Saba Shahin^{1

2}, Mari Perez-Rosendahl^{2

9}; Alzheimer’s Biomarkers Consortium–Down Syndrome (ABC–DS); Elizabeth Head^{2

9}, Kim N Green^{1

2}, Vivek Swarup^{10

11

12}

Affiliations

¹ Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, USA.
² Institute for Memory Impairments and Neurological Disorders (MIND), University of California, Irvine, Irvine, CA, USA.
³ Mathematical, Computational, and Systems Biology (MCSB) Program, University of California, Irvine, Irvine, CA, USA.
⁴ Center for Complex Biological Systems (CCBS), University of California, Irvine, Irvine, CA, USA.
⁵ Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA.
⁶ Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, USA.
⁷ Department of Computer Science, University of California, Irvine, Irvine, CA, USA.
⁸ Department of Pediatrics, University of California, Irvine, School of Medicine, Orange, CA, USA.
⁹ Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA, USA.
¹⁰ Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, USA. vswarup@uci.edu.
¹¹ Institute for Memory Impairments and Neurological Disorders (MIND), University of California, Irvine, Irvine, CA, USA. vswarup@uci.edu.
¹² Center for Complex Biological Systems (CCBS), University of California, Irvine, Irvine, CA, USA. vswarup@uci.edu.

^# Contributed equally.

Abstract

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.

MeSH terms

Aged
Aged, 80 and over
Alzheimer Disease* / genetics
Animals
Cell Communication / genetics
Cell Nucleus / genetics
Disease Models, Animal
Down Syndrome* / genetics
Female
Gene Expression Profiling
Gene Regulatory Networks
Humans
Male
Mice
Transcriptome*

Abstract

MeSH terms

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