Mouse and human microglial phenotypes in Alzheimer’s disease are controlled by amyloid plaque phagocytosis through Hif1α
Open accessAbstract
The important role of microglia, the brain’s resident immune cells, in Alzheimer’s disease (AD) is now well recognized, however their molecular and functional diversity and underlying mechanisms still remain controversial. To transcriptionally and functionally characterize the diversity of microglia in AD and aging, we isolated the amyloid plaque-containing (XO4 + ) and non-containing (XO4 − ) microglia from an AD mouse model. Transcriptomics analysis unveiled independent transcriptional trajectories in ageing and AD. XO4 + microglial transcriptomes linked plaque phagocytosis to altered expression of bona fide late onset AD genetic risk factors. We further revealed that the XO4 + transcriptional program is present in a subset of human microglia from AD patients and is a direct and reversible consequence of Aβ plaque phagocytosis. Conversely, XO4 − microglia in AD displayed an accelerated ageing signature and contained more intracellular post synaptic material than plaque-containing microglia, despite reduced active synaptosome phagocytosis. Mechanistically, we predicted HIF1α as a core regulator of the XO4 − /XO4 + axis, and further validated the mechanism in vitro using human stem cell-derived microglia like cells and primary human microglia. Together these findings unveiled the molecular mechanism underpinning the functional diversity of microglia in AD, providing opportunities to develop treatments targeted at subset specific manipulation of the microglial niche.
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Many disease-associated M4 microglial protein markers were increased in microglia undergoing active amyloid plaque phagocytosis.
“Furthermore, many of the disease-associated M4 microglial protein markers were found to be increased in microglia undergoing active amyloid plaque phagocytosis (Extended Data Figure 10, Supplementary Table 5)33.”
In microglia actively phagocytosing amyloid-β plaques (XO4+), 23 transcripts that were increased overlapped with proteins in the M4 module.
“There were 23 transcripts that overlapped with M4 module members.”
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Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- [85]85. Andrews, T. S. & Hemberg, M. Modelling dropouts allows for unbiased 1388 identification of marker genes in scRNASeq experiments. biorxiv (2016). 1389
Cited by
Sorted by citations
Grubman, A., Chew, G., Ouyang, J. F., Sun, G., Choo, X. Y., McLean, C., Simmons, R. K., Buckberry, S., Vargas-Landin, D. B., Poppe, D., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0539-4 · Cited by 956 · see citing works
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- Authors
- Grubman, A., Choo, X. Y., Chew, G., Ouyang, J. F., Sun, G., Croft, N. P., Rossello, F. J., Simmons, R., Buckberry, S., Landin, D. V., Pflueger, J., Vandekolk, T. H., Abay, Z., Liu, X., Haynes, J. M., McLean, C., Williams, S., Chai, S. Y., Wilson, T., Lister, R., Pouton, C. W., Purcell, A. W., Rackham, O. J. L., Petretto, E., & Polo, J. M.
- Affiliations
- Australian Regenerative Medicine Institute (AU)
- The University of Melbourne (AU)
- National University of Singapore (SG)
- Monash University (AU)
- The University of Western Australia (AU)
- Corresponding author
- Grubman, Alexandra
- Petretto, Enrico
- Polo, Jose M.
- ORCID
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2019-05-17
- OpenAlex
- W2946005609
- Cited by
- 7
- References
- 102
- Citations by year
- 2023: 1 · 2021: 2 · 2020: 3 · 2019: 1
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Funders
- Australian Government
- Monash University
- State Government of Victoria
- Dementia Australia
- Yulgilbar Foundation
- National Health and Medical Research Council
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Alzheimer's disease, microglia, HIF-1α, microglial phenotype, aging, microglial transcriptome, mouse model, genetic risk factors
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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