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Microglia use TAM receptors to detect and engulf amyloid β plaques
Open accessAbstract
Two microglial TAM receptor tyrosine kinases, Axl and Mer, have been linked to Alzheimer's disease, but their roles in disease have not been tested experimentally. We find that in Alzheimer's disease and its mouse models, induced expression of Axl and Mer in amyloid plaque-associated microglia was coupled to induced plaque decoration by the TAM ligand Gas6 and its co-ligand phosphatidylserine. In the APP/PS1 mouse model of Alzheimer's disease, genetic ablation of Axl and Mer resulted in microglia that were unable to normally detect, respond to, organize or phagocytose amyloid-β plaques. These major deficits notwithstanding, TAM-deficient APP/PS1 mice developed fewer dense-core plaques than APP/PS1 mice with normal microglia. Our findings reveal that the TAM system is an essential mediator of microglial recognition and engulfment of amyloid plaques and that TAM-driven microglial phagocytosis does not inhibit, but rather promotes, dense-core plaque development.
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“Microglia are required for the consolidation of neurotoxic soluble Aβ oligomers into more inert insoluble fibrils and for construction into compact plaques (Brown et al., 2020; Huang et al., 2021; Martin et al., 1994).”
From SYK coordinates neuroprotective microglial responses in neurodegenerative disease (2022) · cites this paper as Huang et al., 2021
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Genetic deletion of any of these receptors in mouse models of AD resulted in less compact/more diffuse plaques, and increased neuritic dystrophy around Αβ deposits14,79.”
From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [79]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Furthermore, microglia limit diffuse plaques by constructing and maintaining dense compact-like plaque properties in AD mouse models and humans, thereby blocking the progression of neuritic dystrophy and reducing tau phosphorylation in the local plaque environment [12, 38, 106].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [38]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Interestingly, it was previously reported that filamentous plaques are neurotoxic whereas compact dense-core plaques are relatively benign [38, 52].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [38]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Using the APP/PS1 AD mouse model, Huang et al. showed that genetic ablation of tyrosine kinase TAM receptors inhibited microglial phagocytosis and decreased dense-core plaque density in the cortex and hippocampus after 12 months of age; these changes were not due to any changes in the production of Aβ peptides [38].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [38]
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“Moreover, in AD mouse models, the number of microglia per plaque was reduced when Trem2 or Axl are knocked out, whereas loss of one or both copies of Inpp5d increased the number of microglia that surround plaques [136, 153, 163, 164].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [153]
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“In line with this, activation of AXL and TREM2, while promoting Aβ clearance, were found to increase plaque deposition in separate studies [36, 153].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [153]
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“A prerequisite to detect and engulf Aβ amyloid material is an adequate coverage of the amyloid plaque by glial processes, which involves morphological transformation of astrocytes and microglia upon contact with Aβ amyloid52.”
From Regulation of cell distancing in peri-plaque glial nets by Plexin-B1 affects glial activation and amyloid compaction in Alzheimer’s disease (2024) · cites this paper as [52]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Prior studies proposed that these cells compact amyloid plaques through receptors implicated in phagocytosis such as TREM214, (expressed on myeloid cells and associated to increased AD risk)14,8, AXL, and MER79.”
From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [79]
The cited source says what the claim attributes to it.
In the citing paper
“In line with these observations, mRNA of Axl is strongly upregulated in plaque-associated microglia in AD [153–155].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [153]
The cited source says what the claim attributes to it.
In the citing paper
“Although TAM receptor-signaling has been classically associated with an anti-inflammatory role, TAM receptors mediate Aβ phagocytosis, which in turn promoted development of dense-core plaques [153].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [153]
The cited source says what the claim attributes to it.
In the citing paper
“TREM2 and TAM receptors were suggested to aid in the compaction of amyloid plaques from a diffuse form, which are more neurotoxic and promote neurite dystrophy, to a dense-core form associated with lower neurotoxicity [153, 162, 163].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [153]
The cited source says what the claim attributes to it.
In the citing paper
“As dense-core plaque formation is an outcome of efficient microglial phagocytosis of amyloid material52, the shift of plaques towards dense-core in PB1-KO mice thus agrees with our observations of increased microglial coverage of plaques and augmented microglial function in PB1-KO.”
From Regulation of cell distancing in peri-plaque glial nets by Plexin-B1 affects glial activation and amyloid compaction in Alzheimer’s disease (2024) · cites this paper as [52]
The cited source says what the claim attributes to it.
In the citing paper
“The reduced neuritic dystrophy observed in APP/PS1 PB1-KO mice aligned with the model that dense-core plaques correspond to reduced neurotoxicity due to limited dissemination of neurotoxic soluble Aβ oligomers52.”
From Regulation of cell distancing in peri-plaque glial nets by Plexin-B1 affects glial activation and amyloid compaction in Alzheimer’s disease (2024) · cites this paper as [52]
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In the citing paper
“Also, Mertk which is necessary for detection and engulfment of amyloid plaques by microglia (Huang et al, 2021), and Inpp5d, a known AD risk factor which has a role in limiting plaque formation (Castranio et al, 2023), are downregulated in APOE4.”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Huang et al, 2021
In the citing paper
“some studies have also found that the phagocytosis of Aβ by microglia promoted plaque development.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [152]
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Metadata
- Authors
- Huang, Y., Happonen, K. E., Burrola, P. G., O’Connor, C., Hah, N., Huang, L., Nimmerjahn, A., & Lemke, G.
- Affiliations
- Salk Institute for Biological Studies (US)
- Corresponding author
- Lemke, Greg
- ORCID
- Venue
- Nature Immunology
- Published
- 2021-04-15
- Volume
- 22
- Issue
- 5
- Pages
- 586-594
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC8102389
- OpenAlex
- W3152525961
- Cited by
- 483
- References
- 62
- Citations by year
- 2026: 60 · 2025: 96 · 2024: 99 · 2023: 86 · 2022: 109 · 2021: 33
- FWCI
- 32.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | National Institutes of Health (AG060748, NS083038, NS108034, NS103522, AG062429, CA014195, OD023689)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- microglia, TAM receptors, AXL, Mer, Alzheimer's disease, amyloid plaques, microglial phagocytosis, Gas6, phosphatidylserine, APP/PS1 mice, receptor tyrosine kinase
- MeSH terms
- Intravital Microscopy, c-Mer Tyrosine Kinase, RNA-Seq, Axl Receptor Tyrosine Kinase, Alzheimer Disease, Animals, Brain, Disease Models, Animal, Female, Humans, Male, Phagocytosis, Proto-Oncogene Proteins, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Microglia, Mice, Knockout, Microscopy, Confocal, Receptor Protein-Tyrosine Kinases, Microscopy, Fluorescence, Multiphoton, Mice, Presenilin-1, Single-Cell Analysis
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