PreprintCited by 25Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsSingle-cell and spatial transcriptomics

Uncovering Plaque-Glia Niches in Human Alzheimer’s Disease Brains Using Spatial Transcriptomics

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Avey, Denis R., Ng, Bernard, Vialle, Ricardo A., Kearns, Nicola A., de Paiva Lopes, Katia, Iatrou, Artemis, De Tissera, Sashini, Vyas, Himanshu +7 more·2024·Molecular Neurodegeneration Advances

Preprint — published as 10.1186/s44477-025-00002-z

Abstract

Amyloid-beta (Aβ) plaques and surrounding glial activation are prominent histopathological hallmarks of Alzheimer’s Disease (AD). However, it is unclear how Aβ plaques interact with surrounding glial cells in the human brain. Here, we applied spatial transcriptomics (ST) and immunohistochemistry (IHC) for Aβ, GFAP, and IBA1 to acquire data from 258,987 ST spots within 78 postmortem brain sections of 21 individuals. By coupling ST and adjacent-section IHC, we showed that low Aβ spots exhibit transcriptomic profiles indicative of greater neuronal loss than high Aβ spots, and high-glia spots present transcriptomic changes indicative of more significant inflammation and neurodegeneration. Furthermore, we observed that this ST glial response bears signatures of reported mouse gene modules of plaque-induced genes (PIG), oligodendrocyte (OLIG) response, disease-associated microglia (DAM), and disease-associated astrocytes (DAA), as well as different microglia (MG) states identified in human AD brains, indicating that multiple glial cell states arise around plaques and contribute to local immune response. We then validated the observed effects of Aβ on cell apoptosis and plaque-surrounding glia on inflammation and synaptic loss using IHC. In addition, transcriptomic changes of iPSC-derived microglia-like cells upon short-interval Aβ treatment mimic the ST glial response and mirror the reported activated MG states. Our results demonstrate an exacerbation of synaptic and neuronal loss in low-Aβ or high-glia areas, indicating that microglia response to Aβ-oligomers likely initiates glial activation in plaque-glia niches. Our study lays the groundwork for future pathology genomics studies, opening the door for investigating pathological heterogeneity and causal effects in neurodegenerative diseases.

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  1. Peng T, Thorn K, Schroeder T, Wang L, Theis FJ, Marr C, et al. A BaSiC tool for background and shading correction of optical microscopy images. Nat Commun. 2017;8(1):1-7.
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Authors
Avey, D. R., Ng, B., Vialle, R. A., Kearns, N. A., de Paiva Lopes, K., Iatrou, A., De Tissera, S., Vyas, H., Saunders, D. M., Flood, D. J., Xu, J., Tasaki, S., Gaiteri, C., Bennett, D. A., & Wang, Y.
Affiliations
Rush University Medical Center (US)
Corresponding author
Wang, Yanling
Venue
Molecular Neurodegeneration Advances
Publisher
openRxiv
Published
2024-09-10
Volume
1
Issue
1
Pages
2-2
ISSN
3059-4944 (ISSN-L)
OpenAlex
W4412480976
Cited by
24
References
79
Citations by year
2026: 17 · 2025: 6 · 2024: 1
FWCI
14.80
Type
journal article
Language
en
Open access
Locations
  • Molecular Neurodegeneration Advances (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
National Institute on Aging (R01AG017917, P30 AG72975, P30-AG 10161, R01AG061798, U01‐AG61356, R01AG015819, P30AG010161, R01AG079223, R01AG074082)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
Keywords
Alzheimer's disease, amyloid plaques, glial response, disease-associated microglia, neuronal apoptosis, synaptic loss, iPSC-derived microglia, human brain tissue, spatial transcriptomics, neuroinflammation, neurodegeneration, ROSMAP, single-nucleus RNA sequencing

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