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.
“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
The Discussion (page not provided) suggests that phagocytic microglia construct dense-core plaques from loosely organized Aβ material, and the Results report fewer such plaques when TAM signaling is absent. But the paper frames confinement of toxic pre-plaque oligomers as a hypothesis; it does not establish the claimed conversion of soluble oligomers into more inert insoluble fibrils as a required process. (LLM, conf=0.84)
Experimental — accuracy not yet measuredGenetic deletion of any of these receptors in mouse models of AD results in less compact/more diffuse plaques, and increased neuritic dystrophy around Aβ deposits.
“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]
The Results (“TAM-dependent phagocytosis and shaping of plaques”; page unavailable) report more diffuse plaques and increased markers of dystrophic neuronal membranes after combined Axl and Mertk deletion in APP/PS1 mice. But the paper does not show these outcomes after deletion of any one receptor: in “Dense-core plaque burden in the absence of TAM signaling,” Mertk deletion largely reproduces the reduction in dense-core plaques, whereas Axl deletion does not reduce cortical plaque burden. (LLM, conf=0.90)
Experimental — accuracy not yet measuredMicroglia 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.
“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]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredFilamentous plaques are neurotoxic whereas compact dense-core plaques are relatively benign.
“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]
The Results section reports that markers of dystrophic neuronal membranes increased mainly around diffuse plaques, but also around dense-core plaques. The Discussion proposes that dense-core plaques may confine toxic Aβ oligomers; it does not establish that filamentous plaques are neurotoxic while compact plaques are relatively benign. No page numbers are available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredGenetic 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.
“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]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
In AD mouse models, the number of microglia per plaque is 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.
“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]
The Discussion reports fewer microglia bound per plaque in AD-model mice lacking Trem2 or both Axl and Mertk. It does not establish that Axl knockout alone has that effect, and our copy does not report an increase in plaque-surrounding microglia after loss of Inpp5d (searched: Inpp5d and Axl single-mutant plaque binding). (LLM, conf=0.88)
Experimental — accuracy not yet measuredActivation of AXL and TREM2, while promoting Aβ clearance, increases plaque deposition.
“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]
The Results section, “Dense-core plaque burden in the absence of TAM signaling” (page unavailable), says TAM-mediated phagocytosis promotes dense-core Aβ plaque deposition, but attributes most of that effect to Mer: Axl deletion alone did not reduce cortical plaque burden. The Discussion (page unavailable) says findings on TREM2 deletion and plaque burden are inconsistent, so this paper does not establish that TREM2 activation increases deposition. It documents Aβ engulfment, not necessarily net clearance. (LLM, conf=0.88)
Experimental — accuracy not yet measuredA 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 amyloid.
“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]
The Results (‘Microglial TAM activity at plaques’; page unavailable) describe changes in microglial morphology and plaque-directed processes, while the Discussion links microglial plaque attachment and process responses to engulfment. The paper does not establish adequate coverage by glial processes as a prerequisite for detection and engulfment, or show that astrocytes undergo the claimed morphological transformation upon plaque contact. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPrior studies proposed that plaque-associated microglia compact amyloid plaques through receptors implicated in phagocytosis such as TREM2, AXL, and MER.
“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]
mRNA of Axl is strongly upregulated in plaque-associated microglia in AD.
“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]
TAM receptors mediate Aβ phagocytosis, which in turn promoted development of dense-core plaques.
“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]
TREM2 and TAM receptors aid in the compaction of amyloid plaques from a diffuse form, which is more neurotoxic and promotes neurite dystrophy, to a dense-core form associated with lower neurotoxicity.
“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]
Dense-core plaque formation is an outcome of efficient microglial phagocytosis of amyloid material.
“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]
Dense-core plaques correspond to reduced neurotoxicity due to limited dissemination of neurotoxic soluble Aβ oligomers.
“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]
Mertk and Inpp5d are downregulated in APOE4.
“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
Some studies found that phagocytosis of Aβ by microglia promoted plaque development.
“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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- 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
- Health Sciences › Medicine › Physiology › 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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