Cited by 137Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsSingle-cell and spatial transcriptomics

Microglia-astrocyte crosstalk in the amyloid plaque niche of an Alzheimer’s disease mouse model, as revealed by spatial transcriptomics

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Mallach, Anna, Zielonka, Magdalena, van Lieshout, Veerle, An, Yanru, Khoo, Jia Hui, Vanheusden, Marisa, Chen, Wei-Ting, Moechars, Daan +3 more·2024·Cell Reports

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Abstract

The amyloid plaque niche is a pivotal hallmark of Alzheimer's disease (AD). Here, we employ two high-resolution spatial transcriptomics (ST) platforms, CosMx and Spatial Enhanced Resolution Omics-sequencing (Stereo-seq), to characterize the transcriptomic alterations, cellular compositions, and signaling perturbations in the amyloid plaque niche in an AD mouse model. We discover heterogeneity in the cellular composition of plaque niches, marked by an increase in microglial accumulation. We profile the transcriptomic alterations of glial cells in the vicinity of plaques and conclude that the microglial response to plaques is consistent across different brain regions, while the astrocytic response is more heterogeneous. Meanwhile, as the microglial density of plaque niches increases, astrocytes acquire a more neurotoxic phenotype and play a key role in inducing GABAergic signaling and decreasing glutamatergic signaling in hippocampal neurons. We thus show that the accumulation of microglia around hippocampal plaques disrupts astrocytic signaling, in turn inducing an imbalance in neuronal synaptic signaling.

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Crossref · 10.1016/j.celrep.2024.114216

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  • Different pathological features may generate distinct glial niches, including plaque-associated microglial and astrocytic responses.

    “Recent spatial and single-nucleus studies have emphasized that different pathological features may generate distinct glial niches, including plaque-associated microglial and astrocytic responses [57,58].”

    From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [58]

    The amyloid plaque niche section reports that microglial and astrocytic gene expression changes as the cells approach plaques. The paper supports the plaque-associated example, but the supplied passages do not compare different pathological features or show that they generate distinct glial niches. (LLM, conf=0.84)

    Experimental — accuracy not yet measured
  • Spatial transcriptomic studies of plaque niches have highlighted microglia-astrocyte crosstalk around amyloid deposits.

    “Spatial transcriptomic studies of plaque niches have highlighted microglia–astrocyte crosstalk around amyloid deposits”
  • Microglia may interact with oligodendrocyte-lineage cells in disease-specific ways, as suggested by newer single-nucleus studies across dementia subtypes.

    “newer single-nucleus studies across dementia subtypes suggest that microglia may also interact with oligodendrocyte-lineage cells in disease-specific ways [58,61]”

    From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [58]

    The ‘Cellular effects within the plaque niche’ section reports that microglia and oligodendrocytes are both present in amyloid-plaque niches, but does not establish an interaction between them. The paper examines spatial transcriptomics in an Alzheimer’s mouse model; the passages found do not address single-nucleus studies across dementia subtypes or disease-specific microglia–oligodendrocyte interactions (searched: oligodendrocyte interactions and single-nucleus dementia subtypes). (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 1

  1. Kwakowsk, A., Calvo-Flores Guzman, B., Pandya, M., Turner, C., Waldvo- gel, H.J., and Faull, R.L. (2018). GABAA receptor subunit expression changes in the human Alzheimer's disease hippocampus, subiculum, en- torhinal cortex and superior temporal gyrus. J. Neurochem. 145. https:// doi.org/10.1111/jnc.14179. · DOI

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Authors
Mallach, A., Zielonka, M., van Lieshout, V., An, Y., Khoo, J. H., Vanheusden, M., Chen, W.-T., Moechars, D., Arancibia-Carcamo, I. L., Fiers, M., & De Strooper, B.
Affiliations
  • The Francis Crick Institute (GB)
  • VIB-KU Leuven Center for Brain & Disease Research (BE)
Corresponding author
Fiers, Mark
Venue
Cell Reports
Publisher
Elsevier BV
Published
2024-06
Volume
43
Issue
6
Pages
114216
ISSN
2211-1247 (ISSN-L)
OpenAlex
W4399167645
Cited by
135
References
82
Citations by year
2026: 64 · 2025: 57 · 2024: 14
FWCI
21.06
Type
journal article
Language
en
Open access
Locations
  • Cell Reports (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion, cc-by-nc-nd)
  • Lirias (submittedVersion, cc-by)
  • Figshare (submittedVersion, cc-by)
  • The Francis Crick Institute (cc-by)
Funders
  • European Research Council (ERC-834682 CELLPHASE_AD)
  • Queen Elisabeth Medical Foundation
  • UKRI MRC (UK DRI-1004)
  • VIB
  • Horizon 2020 Framework Programme
  • Dinosaur Research Institute
  • KUL
  • Vlaamse regering
  • Francis Crick Institute
  • UK Dementia Research Institute
  • Fonds Wetenschappelijk Onderzoek
  • Alzheimer's Association
  • Alzheimer’s Research UK
  • Alzheimer's Society
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
Keywords
Alzheimer's disease, amyloid plaques, microglia, astrocytes, hippocampus, GABAergic neurotransmission, glutamatergic signaling, mouse model
MeSH terms
Alzheimer Disease, Animals, Astrocytes, Cell Communication, Disease Models, Animal, Hippocampus, Male, Mice, Transgenic, Neurons, Signal Transduction, Microglia, Mice, Plaque, Amyloid, Transcriptome

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