Uncovering Plaque-Glia Niches in Human Alzheimer’s Disease Brains Using Spatial Transcriptomics
Open accessPreprint — 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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Human spatial studies have identified plaque-glia niches and altered co-expression patterns around amyloid deposits.
“Human spatial studies have already begun to identify plaque-glia niches and altered co-expression patterns around amyloid deposits”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [59]
The immediate plaque microenvironment is molecularly distinct from surrounding tissue.
“suggesting that the immediate plaque microenvironment is molecularly distinct from surrounding tissue [59]”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [59]
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The role of ADAM10 in astrocytes: Implications for Alzheimer’s disease
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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
- ORCID
- Venue
- Molecular Neurodegeneration Advances
- Publisher
- openRxiv
- Published
- 2024-09-10
- Volume
- 1
- Issue
- 1
- Pages
- 2-2
- ISSN
- 3059-4944 (ISSN-L)
- PMC
- PMC12310243
- 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
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- www.biorxiv.org/about/FAQ#license (vor)
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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