Integrative in situ mapping of single-cell transcriptional states and tissue histopathology in a mouse model of Alzheimer's disease

Hu Zeng; Jiahao Huang; Haowen Zhou; William J Meilandt; Borislav Dejanovic; Yiming Zhou; Christopher J Bohlen; Seung-Hye Lee; Jingyi Ren; Albert Liu; Zefang Tang; Hao Sheng; Jia Liu; Morgan Sheng; Xiao Wang

doi:10.1038/s41593-022-01251-x

Integrative in situ mapping of single-cell transcriptional states and tissue histopathology in a mouse model of Alzheimer's disease

Nat Neurosci. 2023 Mar;26(3):430-446. doi: 10.1038/s41593-022-01251-x. Epub 2023 Feb 2.

Authors

Hu Zeng^#^{1

2}, Jiahao Huang^#^{1

2}, Haowen Zhou^#¹, William J Meilandt³, Borislav Dejanovic^{1

4}, Yiming Zhou^{1

2}, Christopher J Bohlen³, Seung-Hye Lee³, Jingyi Ren^{1

2}, Albert Liu², Zefang Tang^{1

2}, Hao Sheng⁵, Jia Liu⁵, Morgan Sheng^{6

7

8}, Xiao Wang^{9

10

11}

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ Department of Neuroscience, Genentech, Inc., South San Francisco, CA, USA.
⁴ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ John A. Paulson School of Engineering and Applied Sciences, Harvard University, Boston, MA, USA.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA, USA. msheng@broadinstitute.org.
⁷ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. msheng@broadinstitute.org.
⁸ Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA. msheng@broadinstitute.org.
⁹ Broad Institute of MIT and Harvard, Cambridge, MA, USA. wangxiao@broadinstitute.org.
¹⁰ Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA. wangxiao@broadinstitute.org.
¹¹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. wangxiao@broadinstitute.org.

^# Contributed equally.

PMID: 36732642
DOI: 10.1038/s41593-022-01251-x

Abstract

Complex diseases are characterized by spatiotemporal cellular and molecular changes that may be difficult to comprehensively capture. However, understanding the spatiotemporal dynamics underlying pathology can shed light on disease mechanisms and progression. Here we introduce STARmap PLUS, a method that combines high-resolution spatial transcriptomics with protein detection in the same tissue section. As proof of principle, we analyze brain tissues of a mouse model of Alzheimer's disease at 8 and 13 months of age. Our approach provides a comprehensive cellular map of disease progression. It reveals a core-shell structure where disease-associated microglia (DAM) closely contact amyloid-β plaques, whereas disease-associated astrocyte-like (DAA-like) cells and oligodendrocyte precursor cells (OPCs) are enriched in the outer shells surrounding the plaque-DAM complex. Hyperphosphorylated tau emerges mainly in excitatory neurons in the CA1 region and correlates with the local enrichment of oligodendrocyte subtypes. The STARmap PLUS method bridges single-cell gene expression profiles with tissue histopathology at subcellular resolution, providing a tool to pinpoint the molecular and cellular changes underlying pathology.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Alzheimer Disease* / genetics
Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Animals
Astrocytes
Brain
Disease Models, Animal
Mice
Mice, Transgenic
Plaque, Amyloid

Substances

Amyloid beta-Peptides
Amyloid beta-Protein Precursor

Grants and funding

DP2 GM146245/GM/NIGMS NIH HHS/United States