TREM2 regulates microglial cholesterol metabolism upon chronic phagocytic challenge
Open accessAbstract
Loss-of-function (LOF) variants of TREM2, an immune receptor expressed in microglia, increase Alzheimer's disease risk. TREM2 senses lipids and mediates myelin phagocytosis, but its role in microglial lipid metabolism is unknown. Combining chronic demyelination paradigms and cell sorting with RNA sequencing and lipidomics, we find that wild-type microglia acquire a disease-associated transcriptional state, while TREM2-deficient microglia remain largely homeostatic, leading to neuronal damage. TREM2-deficient microglia phagocytose myelin debris but fail to clear myelin cholesterol, resulting in cholesteryl ester (CE) accumulation. CE increase is also observed in APOE-deficient glial cells, reflecting impaired brain cholesterol transport. This finding replicates in myelin-treated TREM2-deficient murine macrophages and human iPSC-derived microglia, where it is rescued by an ACAT1 inhibitor and LXR agonist. Our studies identify TREM2 as a key transcriptional regulator of cholesterol transport and metabolism under conditions of chronic myelin phagocytic activity, as TREM2 LOF causes pathogenic lipid accumulation in microglia.
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TREM2 is expressed primarily by microglia in the central nervous system.
“Triggering receptor expressed on myeloid cells 2, a member of the immunoglobulin (Ig) superfamily, is expressed primarily by microglia in the central nervous system”
From PU.1 dictates β-amyloid-induced TREM2 expression upregulation in microglia in a transgenic model of Alzheimer’s disease (2025) · cites this paper as Nugent et al., 2020
TREM2 is a crucial transcriptional regulator of cholesterol transport and lipid metabolism in microglia.
“Chronic demyelination in vivo (12 weeks on CPZ) caused a robust accumulation of cholesteryl ester (CE) and oxidized CE in the Trem2−/– brain, suggesting that TREM2 might be a crucial transcriptional regulator of cholesterol transport and lipid metabolism in microglia [35].”
From TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis (2020) · cites this paper as [35]
Constitutive deletion of Trem2 in mice treated with CPZ exhibited defective clearance of myelin debris and impaired remyelination.
“Conversely, mice with a constitutive deletion of the Trem2 gene treated with CPZ exhibited defective clearance of myelin debris and impaired remyelination (17, 24–26).”
From Acute TREM2 inhibition depletes MAFB-high microglia and hinders remyelination (2025) · cites this paper as [26]
Cholesterol-rich lysosomes and lipid droplets in dysfunctional microglia have been observed in demyelination mouse models and human iPS cell models.
“Cholesterol-rich lysosomes and LDs in dysfunctional microglia have also been observed in the context of demyelination mouse models and human iPS cell models9–12.”
From APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia (2024) · cites this paper as [11]
Several AD-risk genes such as TREM2, APOE, ABCA7, ABCA1, and CLU are directly related to lipid metabolism.
“Several AD-risk genes such as TREM2, APOE, ABCA7, ABCA1, and CLU are directly related to lipid metabolism.26,27,28,29,30,31”
From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [31]
The TREM2 signalling cascade, of which PLCγ2 is a key pathway component, plays an important role in regulating lipid metabolism.
“In addition to binding lipid ligands, the TREM2 signalling cascade, of which PLCγ2 is a key pathway component, plays an important role in regulating lipid metabolism [19, 34].”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [19]
TREM2 KO microglia, both in vivo and in human induced pluripotent stem cells (iPSCs), fail to clear cholesterol esters that accumulate as a result of myelin challenge.
“TREM2 KO microglia, both in vivo and in human induced pluripotent stem cells (iPSCs), fail to clear cholesterol esters that accumulate as a result of myelin challenge [19].”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [19]
In the CNS, TREM2 interacts with a variety of ligands, but it is most notably a receptor for lipid substrates.
“In the CNS, TREM2 interacts with a variety of ligands, but it is most notably a receptor for lipid substrates [17, 19, 48].”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [19]
TREM2 deficiency is known to prevent a conversion of microglia to the disease associated microglial (DAM) state.
“Indeed, TREM2 deficiency is known to prevent a conversion of microglia to the disease associated microglial (DAM) state [19]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [19]
ApoE is the most abundant apolipoprotein in the brain, where it is primarily expressed by astrocytes and reactive microglia, regulating cholesterol metabolism.
“ApoE is the most abundant apolipoprotein in the brain, where it is primarily expressed by astrocytes and reactive microglia7, regulating cholesterol metabolism8,9.”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [9]
Lipid challenges, including cholesterol, can induce pro-inflammatory responses in microglia.
“Lipid challenges, including cholesterol, can induce pro-inflammatory responses in microglia8,9,33.”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [9]
Microglia can change their lipid metabolism in response to the lipid flux that occurs when neurons and OL die in neurodegenerative contexts.
“Microglia can change their lipid metabolism in response to the lipid flux that occurs when neurons and OL die in neurodegenerative contexts [339].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [339]
One function of these secreted HDL-like particles is to supply lipids to neurons via receptor-mediated endocytosis, as well as to assist in lipid export from glia cells.
“It is generally believed that astrocytes are the primary biosynthetic loci of ApoE-containing LNPs, and that one function of these secreted HDL-like particles is to supply lipids to neurons via receptor-mediated endocytosis, as well as to assist in lipid export from glia cells.54”
From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [54]
It is generally believed that astrocytes are the primary biosynthetic loci of ApoE-containing LNPs.
“It is generally believed that astrocytes are the primary biosynthetic loci of ApoE-containing LNPs, and that one function of these secreted HDL-like particles is to supply lipids to neurons via receptor-mediated endocytosis, as well as to assist in lipid export from glia cells.54”
From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [54]
Apolipoproteins, lipids and Aβ itself act as ligands of TREM2 to facilitate microglial phagocytosis and clearance of Aβ and apoptotic neurons.
“Recently, it was further shown that apolipoproteins, lipids and Aβ itself acted as ligands of TREM2 to facilitate microglial phagocytosis and clearance of Aβ and apoptotic neurons (32–35).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [35]
Trem2 knockdown decreasing survival and altering metabolism of microglia is consistent with previous studies.
“The knockdown of Trem2 decreasing survival and altering the metabolism of microglia is consistent with previous studies (35,38–40,56,57).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [35]
Other studies have not revealed obvious phenotypes in young Trem2 R47H expressing mice, or even Trem2 knockout mice, unless they are aged or bred to amyloid mouse models.
“Other studies have not revealed obvious phenotypes in young Trem2 R47H expressing mice, or even Trem2 knockout mice, unless they are aged or bred to amyloid mouse models (35,61,85–87).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [35]
Microglia change their lipid metabolism in response to the lipid flux that occurs when neurons and oligodendrocytes die in neurodegenerative contexts.
“microglia change their lipid metabolism in response to the lipid flux that occurs when neurons and oligodendrocytes die in neurodegenerative contexts27”
From Neurotoxic reactive astrocytes induce cell death via saturated lipids (2021) · cites this paper as [27]
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Microglia: Immune and non-immune functions
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Emerging Microglia Biology Defines Novel Therapeutic Approaches for Alzheimer’s Disease
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Molecular and metabolic heterogeneity of astrocytes and microglia
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TREM2: Potential therapeutic targeting of microglia for Alzheimer's disease
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Self-citationTREM2 regulates microglial lipid droplet formation and represses post-ischemic brain injury
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Mitochondrial Regulation of Microglial Immunometabolism in Alzheimer’s Disease
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Leveraging preclinical models for the development of Alzheimer disease therapeutics
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Self-citationTREM2 protects from atherosclerosis by limiting necrotic core formation
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25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner
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Control of immune cell function by the unfolded protein response
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Vascular dementia: A microglia's perspective
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Microglia heterogeneity, modeling and cell-state annotation in development and neurodegeneration
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TREM2 promotes cholesterol uptake and foam cell formation in atherosclerosis
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- Authors
- Nugent, A. A., Lin, K., van Lengerich, B., Lianoglou, S., Przybyla, L., Davis, S. S., Llapashtica, C., Wang, J., Kim, D. J., Xia, D., Lucas, A., Baskaran, S., Haddick, P. C. G., Lenser, M., Earr, T. K., Shi, J., Dugas, J. C., Andreone, B. J., Logan, T., Solanoy, H. O., Chen, H., Srivastava, A., Poda, S. B., Sanchez, P. E., Watts, R. J., Sandmann, T., Astarita, G., Lewcock, J. W., Monroe, K. M., & Di Paolo, G.
- Affiliations
- Denali Therapeutics (United States) (US)
- Corresponding author
- Monroe, Kathryn M.
- ORCID
- Lin, Karin
- Lianoglou, Steve
- Przybyla, Laralynne
- Davis, Sonnet S.
- Wang, Junhua
- Kim, Do Jin
- Earr, Timothy K.
- Shi, Ju
- Dugas, Jason C.
- Andreone, Benjamin J.
- Logan, Todd
- Solanoy, Hilda O.
- Srivastava, Ankita
- Poda, Suresh B.
- Sanchez, Pascal E.
- Watts, Ryan J.
- Sandmann, Thomas
- Astarita, Giuseppe
- Lewcock, Joseph W.
- Monroe, Kathryn M.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2020-03
- Volume
- 105
- Issue
- 5
- Pages
- 837-854.e9
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2981166078
- Cited by
- 745
- References
- 90
- Citations by year
- 2026: 129 · 2025: 131 · 2024: 113 · 2023: 131 · 2022: 101 · 2021: 87 · 2020: 50 · 2018: 1
- FWCI
- 22.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- SSRN Electronic Journal (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Denali Therapeutics.
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- TREM2, microglia, cholesterol metabolism, myelin phagocytosis, demyelination, cholesteryl ester accumulation, apolipoprotein E, ACAT1, LXR agonists, Alzheimer's disease risk, lipidomics, neuronal injury, myelin debris clearance
- MeSH terms
- Liver X Receptors, Mice, Knockout, ApoE, RNA-Seq, Lipidomics, Acetyl-CoA C-Acetyltransferase, Alzheimer Disease, Animals, Brain, Cholesterol, Cholesterol Esters, Disease Models, Animal, Flow Cytometry, Humans, Macrophages, Membrane Glycoproteins, Myelin Sheath, Phagocytosis, Receptors, Immunologic, Microglia, Mice, Knockout, Lipid Metabolism, Mice, Induced Pluripotent Stem Cells
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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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