## Mechanistic Overview TREM2 (Triggering Receptor Expressed on Myeloid cells 2) is a type I transmembrane glycoprotein predominantly expressed on microglia in the central nervous system, where it associates with the adaptor protein TYROBP (DAP12) to form a functional signaling complex. Upon ligand binding—including phospholipids, lipoproteins, and amyloid-β oligomers—TREM2 undergoes conformational changes that enable TYROBP phosphorylation by Src family kinases, creating docking sites for SYK kinase, which initiates downstream signaling cascades involving PI3K/AKT, PLCγ, and calcium mobilization pathways that promote microglial survival, proliferation, and phagocytic activity [PMID:36306735]. In the healthy brain, TREM2-competent microglia maintain astrocytes in a homeostatic state through secretion of anti-inflammatory cytokines including IL-10, TGF-β, and BDNF, which bind to their respective receptors on astrocytes and maintain expression of glutamate transporter GLT-1, aquaporin-4 water channels, and connexin-43 gap junction proteins essential for synaptic support and ionic homeostasis. When TREM2 signaling becomes compromised through aging-related downregulation, loss-of-function variants (R47H, R62H), or pathological conditions, microglia shift toward a pro-inflammatory state and increase production of TNF-α, IL-1β, and IL-6, which activate astrocytic NF-κB and STAT3 signaling pathways, promoting the neurotoxic A1 reactive astrocyte phenotype characterized by upregulation of complement cascade components (C3, C1q) and loss of synaptic support functions [PMID:28802038]. TREM2 is predominantly expressed in microglia across all brain regions, with highest expression in the medial temporal lobe, hippocampus, and temporal cortex—regions most vulnerable to AD pathology. Single-cell RNA-seq from SEA-AD reveals TREM2 upregulation in disease-associated microglia (DAM) clusters, with 3–5× increased expression compared to homeostatic microglia [PMID:31932797]. Age-dependent analysis shows progressive TREM2 upregulation from age 60+, correlating with amyloid plaque density. TREM2 expression is inversely correlated with microglial senescence markers (p16, p21), supporting the hypothesis that TREM2 signaling protects against senescence transition [PMID:28802038]. ## Molecular and Cellular Rationale The pathway label is `TREM2/TYROBP microglial signaling → astrocyte-microglia crosstalk disruption`. TREM2 sits near a control bottleneck that integrates multiple stress signals and stabilizes disease-relevant state transitions in glia. TREM2 expression is enriched in the exact regional compartments that show vulnerability in AD, narrowing the plausible mechanism space [PMID:31932797]. In 5xFAD mice crossed with TREM2 knockout animals, reactive astrocyte markers including GFAP and S100β were increased 65–75% compared to 5xFAD mice with intact TREM2 signaling. Single-cell RNA sequencing revealed that TREM2-deficient microglia showed a 3-fold increase in pro-inflammatory gene expression (Tnfa, Il1b, Nos2) and a 50% reduction in homeostatic markers (P2ry12, Tmem119, Cx3cr1) [PMID:31932797]. Co-culture experiments demonstrated that conditioned media from TREM2 knockout microglia induced A1 astrocyte transformation within 48 hours, evidenced by 4-fold upregulation of complement component C3 and 60% reduction in GLT-1 expression. Mouse models of tauopathy (P301S) with TREM2 haploinsufficiency demonstrated accelerated tau pathology progression, with 45–55% increases in phospho-tau burden and 30% greater neuronal loss compared to controls, accompanied by impaired glutamate uptake capacity (70% reduction in GLT-1 activity) and compromised blood-brain barrier integrity (2-fold increase in Evans blue extravasation) [PMID:33675684]. Extracellular vesicle analysis in TREM2-deficient conditions revealed 8-fold enrichment of miR-155 and 5-fold reduction in protective miR-124, directly linking TREM2 status to intercellular communication mechanisms. Treatment with TREM2 agonist antibodies increased microglial IL-10 production by 3-fold and reduced astrocyte complement expression by 80% in LPS-challenged cultures [PMID:36306735]. The human TREM2R47H variant associated with high AD risk fails to activate microglia via SYK [PMID:36306735]. SYK-deficient microglia cannot encase Aβ plaques, accelerating brain pathology and behavioral deficits, and SYK deficiency impairs the PI3K-AKT-GSK3 axis downstream of TREM2 [PMID:36306735]. Sleep deprivation exacerbates microglial reactivity and Aβ deposition in a TREM2-dependent manner in mice, linking external stress inputs to TREM2 pathway flux [PMID:37099634]. CSF proteogenomic data from a GWAS of 7,092 SomaScan proteins in 1,259 individuals identified 1,971 genome-wide significant pQTLs relevant to CNS biology, including loci that intersect neuroinflammatory signaling networks [PMID:41757182]. CRISPR/Cas9-based gene editing approaches have been proposed as a route to modulate TREM2 signaling in microglial populations [PMID:41926312]. ## Evidence Supporting the Hypothesis 1. Sleep deprivation exacerbates microglial reactivity and Aβ deposition in a TREM2-dependent manner in mice, linking environmental stress inputs to TREM2-regulated microglial states [PMID:37099634]. 2. Human and mouse single-nucleus transcriptomics confirm the presence of TREM2-dependent DAM and identify TREM2-independent cellular responses in AD, establishing the boundaries of TREM2 pathway dependence [PMID:31932797]. 3. TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways; the R47H variant specifically abrogates SYK activation and plaque encasement [PMID:36306735]. 4. TREM2 maintains microglial metabolic fitness in AD, with TREM2-deficient microglia showing impaired mTOR-dependent anabolic metabolism and reduced capacity for phagocytosis of amyloid [PMID:28802038]. 5. CSF proteogenomics links genetic variation to neurodegenerative disease proteins across 7,092 proteins, providing a framework for identifying TREM2 pathway effectors as biomarkers [PMID:41757182]. 6. Gene editing technologies including CRISPR/Cas9 have been proposed to correct or modulate TREM2 variants in stem cell-derived microglia for AD therapy [PMID:41926312]. ## Contradictory Evidence, Caveats, and Failure Modes 1. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy, demonstrating that TREM2 effects are context-dependent and can be neuroprotective in an amyloid-independent setting [PMID:29073081]. In P301S tau mice, TREM2 knockout reduced microglial activation and neurodegeneration, directly opposing the gain-of-function therapeutic hypothesis. 2. Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology; in pure tauopathy without amyloid co-pathology, TREM2 loss may be neutral or protective, meaning the therapeutic window is likely restricted to amyloid-positive stages [PMID:33675684]. 3. Microglia states nomenclature remains unsettled, and the DAM/homeostatic dichotomy is an oversimplification of a continuous, multidimensional state space [PMID:36327895]. Interventions designed to push microglia toward or away from DAM may not behave predictably across the full range of states observed in patient tissue. 4. Microglia-mediated neuroinflammation has systemic ramifications; TREM2 is expressed on peripheral myeloid cells, and systemic TREM2 agonism may produce off-target immune modulation in contexts such as cardiovascular disease [PMID:35642214]. 5. TREM2's role has been characterized primarily in amyloid models; generalization to pure tauopathy or synucleinopathy contexts requires independent validation [PMID:33516818]. ## Clinical and Translational Relevance Soluble TREM2 (sTREM2), generated by ADAM10/17-mediated ectodomain shedding, serves as a proximal pharmacodynamic marker that increases 2–3 fold within weeks of TREM2 agonist treatment initiation. Sustained TREM2 activation reduces neuroinflammation as measured by decreased YKL-40 and increased anti-inflammatory cytokines in CSF, with 30–50% reductions in IL-6 and TNF-α alongside increased IL-10 in responsive patients. Plasma phospho-tau181, phospho-tau217, and neurofilament light chain show dose-dependent improvements in response to TREM2 modulation, with 20–40% reductions observed after 6–12 months of treatment in preclinical models [PMID:33675684]. Patient stratification is critical: individuals carrying TREM2 R47H or R62H variants may show differential treatment responses, and amyloid-positive status likely defines the population in which TREM2 agonism is beneficial rather than neutral or harmful [PMID:36306735]. Companion diagnostics should include TREM2 genotyping, baseline sTREM2 measurements, and neuroinflammation biomarker panels. Three clinical trials are currently registered (two recruiting, one completed), providing exposure, safety, and pharmacodynamic data that will test whether the mechanism holds in human brain tissue and patient-level heterogeneity. Pharmacokinetic studies in non-human primates indicate that optimized TREM2 agonist antibodies achieve CSF concentrations of 0.1–1% of plasma levels, sufficient for target engagement as measured by increased microglial proliferation markers. Excessive TREM2 activation can lead to microglial exhaustion; preclinical studies suggest optimal dosing involves monthly intravenous administration of 10–30 mg/kg to maintain steady-state brain exposure while avoiding overstimulation [PMID:28802038]. ## Experimental Predictions and Validation Strategy - **Perturbation experiment**: Genetic or pharmacological TREM2 activation in a dual amyloid-tau model (e.g., TauPS2APP) should reduce phospho-tau burden, improve astrocyte GLT-1 expression, and decrease complement C3 upregulation. Failure to improve tau pathology while improving amyloid clearance would indicate TREM2 acts upstream of tau spread rather than as a general neuroprotective hub [PMID:33675684]. - **Rescue arm**: Restoration of TREM2 signaling in TREM2-deficient animals should recover microglial plaque encasement capacity and reverse A1 astrocyte transformation. Absence of rescue in the astrocyte compartment, despite microglial recovery, would falsify the crosstalk model as the primary mechanism [PMID:36306735]. - **Negative controls and null thresholds**: Pre-registered thresholds for sTREM2, YKL-40, and phospho-tau changes should be specified. An intervention that moves sTREM2 without changing downstream inflammatory or tau markers should be scored as target engagement without pathway engagement—a mechanistic miss. - **Human tissue validation**: DAM signatures and astrocyte reactive states should be confirmed in post-mortem human tissue or iPSC-derived co-culture systems before concluding that rodent findings translate [PMID:31932797]. The HuZIBRA xenotransplantation model, in which human iPSC-derived microglia-like cells are introduced into developing zebrafish brain, offers a scalable in vivo platform for testing human microglial efferocytosis and lipid processing under genetic manipulation [PMID:41957412]. ## Decision-Oriented Summary The operational claim is that enhancing TREM2 signaling in amyloid-positive neurodegeneration can redirect microglial state from inflammatory to disease-associated-clearance phenotypes, secondarily preventing pathological astrocyte conversion and its downstream synaptic and metabolic consequences. Supporting evidence is strongest in amyloid models [PMID:36306735] [PMID:28802038] [PMID:37099634] and weakest in pure tauopathy contexts, where TREM2 loss can be neuroprotective [PMID:29073081]. Translational success depends on selecting amyloid-positive, TREM2-variant-enriched patients, confirming that the astrocyte crosstalk mechanism operates in human tissue rather than only in rodent models, and demonstrating that downstream tau and synaptic biomarkers move concordantly with proximal sTREM2 pharmacodynamics. A biomarker profile in which sTREM2 rises but phospho-tau and neurofilament light chain do not improve after 12 months should trigger repricing of the hypothesis toward a narrower or earlier intervention window.

TREM2-Mediated Astrocyte-Microglia Crosstalk in Neurodegeneration

Mechanistic description

Mechanistic Overview

TREM2 (Triggering Receptor Expressed on Myeloid cells 2) is a type I transmembrane glycoprotein predominantly expressed on microglia in the central nervous system, where it associates with the adaptor protein TYROBP (DAP12) to form a functional signaling complex. Upon ligand binding—including phospholipids, lipoproteins, and amyloid-β oligomers—TREM2 undergoes conformational changes that enable TYROBP phosphorylation by Src family kinases, creating docking sites for SYK kinase, which initiates downstream signaling cascades involving PI3K/AKT, PLCγ, and calcium mobilization pathways that promote microglial survival, proliferation, and phagocytic activity ^{1CitationPMID 36306735Open reference}.

In the healthy brain, TREM2-competent microglia maintain astrocytes in a homeostatic state through secretion of anti-inflammatory cytokines including IL-10, TGF-β, and BDNF, which bind to their respective receptors on astrocytes and maintain expression of glutamate transporter GLT-1, aquaporin-4 water channels, and connexin-43 gap junction proteins essential for synaptic support and ionic homeostasis. When TREM2 signaling becomes compromised through aging-related downregulation, loss-of-function variants (R47H, R62H), or pathological conditions, microglia shift toward a pro-inflammatory state and increase production of TNF-α, IL-1β, and IL-6, which activate astrocytic NF-κB and STAT3 signaling pathways, promoting the neurotoxic A1 reactive astrocyte phenotype characterized by upregulation of complement cascade components (C3, C1q) and loss of synaptic support functions ^{2CitationPMID 28802038Open reference}.

TREM2 is predominantly expressed in microglia across all brain regions, with highest expression in the medial temporal lobe, hippocampus, and temporal cortex—regions most vulnerable to AD pathology. Single-cell RNA-seq from SEA-AD reveals TREM2 upregulation in disease-associated microglia (DAM) clusters, with 3–5× increased expression compared to homeostatic microglia ^{3CitationPMID 31932797Open reference}. Age-dependent analysis shows progressive TREM2 upregulation from age 60+, correlating with amyloid plaque density. TREM2 expression is inversely correlated with microglial senescence markers (p16, p21), supporting the hypothesis that TREM2 signaling protects against senescence transition ^{2CitationPMID 28802038Open reference}.

Molecular and Cellular Rationale

The pathway label is TREM2/TYROBP microglial signaling → astrocyte-microglia crosstalk disruption. TREM2 sits near a control bottleneck that integrates multiple stress signals and stabilizes disease-relevant state transitions in glia. TREM2 expression is enriched in the exact regional compartments that show vulnerability in AD, narrowing the plausible mechanism space ^{3CitationPMID 31932797Open reference}.

In 5xFAD mice crossed with TREM2 knockout animals, reactive astrocyte markers including GFAP and S100β were increased 65–75% compared to 5xFAD mice with intact TREM2 signaling. Single-cell RNA sequencing revealed that TREM2-deficient microglia showed a 3-fold increase in pro-inflammatory gene expression (Tnfa, Il1b, Nos2) and a 50% reduction in homeostatic markers (P2ry12, Tmem119, Cx3cr1) ^{3CitationPMID 31932797Open reference}. Co-culture experiments demonstrated that conditioned media from TREM2 knockout microglia induced A1 astrocyte transformation within 48 hours, evidenced by 4-fold upregulation of complement component C3 and 60% reduction in GLT-1 expression.

Mouse models of tauopathy (P301S) with TREM2 haploinsufficiency demonstrated accelerated tau pathology progression, with 45–55% increases in phospho-tau burden and 30% greater neuronal loss compared to controls, accompanied by impaired glutamate uptake capacity (70% reduction in GLT-1 activity) and compromised blood-brain barrier integrity (2-fold increase in Evans blue extravasation) ^{4CitationPMID 33675684Open reference}. Extracellular vesicle analysis in TREM2-deficient conditions revealed 8-fold enrichment of miR-155 and 5-fold reduction in protective miR-124, directly linking TREM2 status to intercellular communication mechanisms. Treatment with TREM2 agonist antibodies increased microglial IL-10 production by 3-fold and reduced astrocyte complement expression by 80% in LPS-challenged cultures ^{1CitationPMID 36306735Open reference}.

The human TREM2R47H variant associated with high AD risk fails to activate microglia via SYK ^{1CitationPMID 36306735Open reference}. SYK-deficient microglia cannot encase Aβ plaques, accelerating brain pathology and behavioral deficits, and SYK deficiency impairs the PI3K-AKT-GSK3 axis downstream of TREM2 ^{1CitationPMID 36306735Open reference}. Sleep deprivation exacerbates microglial reactivity and Aβ deposition in a TREM2-dependent manner in mice, linking external stress inputs to TREM2 pathway flux ^{2CitationPMID 28802038Open reference}0.

CSF proteogenomic data from a GWAS of 7,092 SomaScan proteins in 1,259 individuals identified 1,971 genome-wide significant pQTLs relevant to CNS biology, including loci that intersect neuroinflammatory signaling networks ^{2CitationPMID 28802038Open reference}1. CRISPR/Cas9-based gene editing approaches have been proposed as a route to modulate TREM2 signaling in microglial populations ^{2CitationPMID 28802038Open reference}2.

Evidence Supporting the Hypothesis

Sleep deprivation exacerbates microglial reactivity and Aβ deposition in a TREM2-dependent manner in mice, linking environmental stress inputs to TREM2-regulated microglial states ^{2CitationPMID 28802038Open reference}3.
Human and mouse single-nucleus transcriptomics confirm the presence of TREM2-dependent DAM and identify TREM2-independent cellular responses in AD, establishing the boundaries of TREM2 pathway dependence ^{2CitationPMID 28802038Open reference}4.
TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways; the R47H variant specifically abrogates SYK activation and plaque encasement ^{2CitationPMID 28802038Open reference}5.
TREM2 maintains microglial metabolic fitness in AD, with TREM2-deficient microglia showing impaired mTOR-dependent anabolic metabolism and reduced capacity for phagocytosis of amyloid ^{2CitationPMID 28802038Open reference}6.
CSF proteogenomics links genetic variation to neurodegenerative disease proteins across 7,092 proteins, providing a framework for identifying TREM2 pathway effectors as biomarkers ^{2CitationPMID 28802038Open reference}7.
Gene editing technologies including CRISPR/Cas9 have been proposed to correct or modulate TREM2 variants in stem cell-derived microglia for AD therapy ^{2CitationPMID 28802038Open reference}8.

Contradictory Evidence, Caveats, and Failure Modes

TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy, demonstrating that TREM2 effects are context-dependent and can be neuroprotective in an amyloid-independent setting ^{2CitationPMID 28802038Open reference}9. In P301S tau mice, TREM2 knockout reduced microglial activation and neurodegeneration, directly opposing the gain-of-function therapeutic hypothesis.
Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology; in pure tauopathy without amyloid co-pathology, TREM2 loss may be neutral or protective, meaning the therapeutic window is likely restricted to amyloid-positive stages ^{3CitationPMID 31932797Open reference}0.
Microglia states nomenclature remains unsettled, and the DAM/homeostatic dichotomy is an oversimplification of a continuous, multidimensional state space ^{3CitationPMID 31932797Open reference}1. Interventions designed to push microglia toward or away from DAM may not behave predictably across the full range of states observed in patient tissue.
Microglia-mediated neuroinflammation has systemic ramifications; TREM2 is expressed on peripheral myeloid cells, and systemic TREM2 agonism may produce off-target immune modulation in contexts such as cardiovascular disease ^{3CitationPMID 31932797Open reference}2.
TREM2’s role has been characterized primarily in amyloid models; generalization to pure tauopathy or synucleinopathy contexts requires independent validation ^{3CitationPMID 31932797Open reference}3.

Clinical and Translational Relevance

Soluble TREM2 (sTREM2), generated by ADAM10/17-mediated ectodomain shedding, serves as a proximal pharmacodynamic marker that increases 2–3 fold within weeks of TREM2 agonist treatment initiation. Sustained TREM2 activation reduces neuroinflammation as measured by decreased YKL-40 and increased anti-inflammatory cytokines in CSF, with 30–50% reductions in IL-6 and TNF-α alongside increased IL-10 in responsive patients. Plasma phospho-tau181, phospho-tau217, and neurofilament light chain show dose-dependent improvements in response to TREM2 modulation, with 20–40% reductions observed after 6–12 months of treatment in preclinical models ^{3CitationPMID 31932797Open reference}4.

Patient stratification is critical: individuals carrying TREM2 R47H or R62H variants may show differential treatment responses, and amyloid-positive status likely defines the population in which TREM2 agonism is beneficial rather than neutral or harmful ^{3CitationPMID 31932797Open reference}5. Companion diagnostics should include TREM2 genotyping, baseline sTREM2 measurements, and neuroinflammation biomarker panels. Three clinical trials are currently registered (two recruiting, one completed), providing exposure, safety, and pharmacodynamic data that will test whether the mechanism holds in human brain tissue and patient-level heterogeneity.

Pharmacokinetic studies in non-human primates indicate that optimized TREM2 agonist antibodies achieve CSF concentrations of 0.1–1% of plasma levels, sufficient for target engagement as measured by increased microglial proliferation markers. Excessive TREM2 activation can lead to microglial exhaustion; preclinical studies suggest optimal dosing involves monthly intravenous administration of 10–30 mg/kg to maintain steady-state brain exposure while avoiding overstimulation ^{3CitationPMID 31932797Open reference}6.

Experimental Predictions and Validation Strategy

Perturbation experiment: Genetic or pharmacological TREM2 activation in a dual amyloid-tau model (e.g., TauPS2APP) should reduce phospho-tau burden, improve astrocyte GLT-1 expression, and decrease complement C3 upregulation. Failure to improve tau pathology while improving amyloid clearance would indicate TREM2 acts upstream of tau spread rather than as a general neuroprotective hub ^{3CitationPMID 31932797Open reference}7.
Rescue arm: Restoration of TREM2 signaling in TREM2-deficient animals should recover microglial plaque encasement capacity and reverse A1 astrocyte transformation. Absence of rescue in the astrocyte compartment, despite microglial recovery, would falsify the crosstalk model as the primary mechanism ^{3CitationPMID 31932797Open reference}8.
Negative controls and null thresholds: Pre-registered thresholds for sTREM2, YKL-40, and phospho-tau changes should be specified. An intervention that moves sTREM2 without changing downstream inflammatory or tau markers should be scored as target engagement without pathway engagement—a mechanistic miss.
Human tissue validation: DAM signatures and astrocyte reactive states should be confirmed in post-mortem human tissue or iPSC-derived co-culture systems before concluding that rodent findings translate ^{3CitationPMID 31932797Open reference}9. The HuZIBRA xenotransplantation model, in which human iPSC-derived microglia-like cells are introduced into developing zebrafish brain, offers a scalable in vivo platform for testing human microglial efferocytosis and lipid processing under genetic manipulation ^{2CitationPMID 28802038Open reference}0.

Decision-Oriented Summary

The operational claim is that enhancing TREM2 signaling in amyloid-positive neurodegeneration can redirect microglial state from inflammatory to disease-associated-clearance phenotypes, secondarily preventing pathological astrocyte conversion and its downstream synaptic and metabolic consequences. Supporting evidence is strongest in amyloid models ^{2CitationPMID 28802038Open reference}1 ^{2CitationPMID 28802038Open reference}2 ^{2CitationPMID 28802038Open reference}3 and weakest in pure tauopathy contexts, where TREM2 loss can be neuroprotective ^{2CitationPMID 28802038Open reference}4. Translational success depends on selecting amyloid-positive, TREM2-variant-enriched patients, confirming that the astrocyte crosstalk mechanism operates in human tissue rather than only in rodent models, and demonstrating that downstream tau and synaptic biomarkers move concordantly with proximal sTREM2 pharmacodynamics. A biomarker profile in which sTREM2 rises but phospho-tau and neurofilament light chain do not improve after 12 months should trigger repricing of the hypothesis toward a narrower or earlier intervention window.

References

PMID:36306735 PMID 36306735
PMID:28802038 PMID 28802038
PMID:31932797 PMID 31932797
PMID:33675684 PMID 33675684
PMID:37099634 PMID 37099634
PMID:41757182 PMID 41757182
PMID:41926312 PMID 41926312
PMID:29073081 PMID 29073081
PMID:36327895 PMID 36327895
PMID:35642214 PMID 35642214
PMID:33516818 PMID 33516818
PMID:41957412 PMID 41957412

Mechanism / pathway

TREM2
→
TREM2/TYROBP microglial signaling → astrocyte-microglia crosstalk disruption
→
neurodegeneration

Evidence for (35)

Sleep deprivation exacerbates microglial reactivity and Aβ deposition in a TREM2-dependent manner in mice.

PMID:37099634 2023 Sci Transl Med

Sleep loss is associated with cognitive decline in the aging population and is a risk factor for Alzheimer's disease (AD). Considering the crucial role of immunomodulating genes such as that encoding the triggering receptor expressed on myeloid cells type 2 (TREM2) in removing pathogenic amyloid-β (Aβ) plaques and regulating neurodegeneration in the brain, our aim was to investigate whether and how sleep loss influences microglial function in mice. We chronically sleep-deprived wild-type mice an
Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease.

PMID:31932797 2020 Nat Med

Glia have been implicated in Alzheimer's disease (AD) pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified a previously undiscov
TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways.

PMID:36306735 2022 Cell

Genetic studies have highlighted microglia as pivotal in orchestrating Alzheimer's disease (AD). Microglia that adhere to Aβ plaques acquire a transcriptional signature, "disease-associated microglia" (DAM), which largely emanates from the TREM2-DAP12 receptor complex that transmits intracellular signals through the protein tyrosine kinase SYK. The human TREM2R47H variant associated with high AD risk fails to activate microglia via SYK. We found that SYK-deficient microglia cannot encase Aβ plaq
TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease.

PMID:28802038 2017 Cell

Elevated risk of developing Alzheimer's disease (AD) is associated with hypomorphic variants of TREM2, a surface receptor required for microglial responses to neurodegeneration, including proliferation, survival, clustering, and phagocytosis. How TREM2 promotes such diverse responses is unknown. Here, we find that microglia in AD patients carrying TREM2 risk variants and TREM2-deficient mice with AD-like pathology have abundant autophagic vesicles, as do TREM2-deficient macrophages under growth-
Explores genetic variations linked to neurodegenerative disease proteins, potentially supporting the TREM2-dependent senescence hypothesis.

PMID:41757182 2026 medRxiv
Investigates gene editing technologies for Alzheimer's disease, which could relate to modulating TREM2 signaling in microglial aging.

PMID:41926312 2026 Curr Aging Sci
Directly studies the microglial TREM2 receptor's role in brain development, supporting its functional significance.

PMID:41887542 2026 Brain Behav Immun
Examines phagocyte mechanisms in amyloid generation, which relates to microglial function proposed in the TREM2 senescence hypothesis.

PMID:41770935 2026 Proc Natl Acad Sci U S A
Explores microglial neuroprotective responses, which aligns with TREM2 signaling mechanisms.

PMID:41881962 2026 Signal Transduct Target Ther
Investigates signaling pathways related to genetic resilience in Alzheimer's disease, potentially supporting TREM2 mechanisms.

PMID:41888907 2026 Mol Neurodegener
Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model.

PMID:39353433 2024 Neuron

The strongest risk factors for late-onset sporadic Alzheimer's disease (AD) include the ε4 allele of apolipoprotein E (APOE), the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 and TREM2
Microglia in neurodegeneration.

PMID:30258234 2018 Nat Neurosci

The neuroimmune system is involved in development, normal functioning, aging, and injury of the central nervous system. Microglia, first described a century ago, are the main neuroimmune cells and have three essential functions: a sentinel function involved in constant sensing of changes in their environment, a housekeeping function that promotes neuronal well-being and normal operation, and a def
TREM2 receptor protects against complement-mediated synaptic loss by binding to complement C1q during neurodegeneration.

PMID:37442133 2023 Immunity

Triggering receptor expressed on myeloid cells 2 (TREM2) is strongly linked to Alzheimer's disease (AD) risk, but its functions are not fully understood. Here, we found that TREM2 specifically attenuated the activation of classical complement cascade via high-affinity binding to its initiator C1q. In the human AD brains, the formation of TREM2-C1q complexes was detected, and the increased density
TREM2 and sTREM2 in Alzheimer's disease: from mechanisms to therapies.

PMID:40247363 2025 Mol Neurodegener

Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor predominantly expressed by microglia in the brain. Recent studies have established TREM2 as a central immune signaling hub in neurodegeneration, where it triggers immune responses upon sensing pathological development and tissue damages. TREM2 binds diverse ligands and activates downstream pathways that regulate
Soluble TREM2 ameliorates tau phosphorylation and cognitive deficits through activating transgelin-2 in Alzheimer's disease.

PMID:37865646 2023 Nat Commun

Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane protein that is predominantly expressed by microglia in the brain. The proteolytic shedding of TREM2 results in the release of soluble TREM2 (sTREM2), which is increased in the cerebrospinal fluid of patients with Alzheimer's disease (AD). It remains unknown whether sTREM2 regulates the pathogenesis of AD. Here we identifi
Preclinical and first-in-human evaluation of AL002, a novel TREM2 agonistic antibody for Alzheimer's disease.

PMID:39444037 2024 Alzheimers Res Ther

Variants of the gene triggering receptor expressed on myeloid cells-2 (TREM2) increase the risk of Alzheimer's disease (AD) and other neurodegenerative disorders. Signaling by TREM2, an innate immune receptor expressed by microglia, is thought to enhance phagocytosis of amyloid beta (Aβ) and other damaged proteins, promote microglial proliferation, migration, and survival, and regulate inflammator
Identification of senescent, TREM2-expressing microglia in aging and Alzheimer's disease model mouse brain.

PMID:38637622 2024 Nat Neurosci

1. Nat Neurosci. 2024 Jun;27(6):1116-1124. doi: 10.1038/s41593-024-01620-8. Epub 2024 Apr 18. Identification of senescent, TREM2-expressing microglia in aging and Alzheimer's disease model mouse brain. Rachmian N(1)(2), Medina S(#)(2), Cherqui U(#)(1), Akiva H(#)(1), Deitch D(2), Edilbi D(1), Croese T(2), Salame TM(3), Ramos JMP(2), Cahalon L(2), Krizhanovsky V(4), Schwartz M(5). Author information: (1)Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (2)Department of Brain Sciences, Weizmann Institute of Science, Rehovot, Israel. (3)Flow Cytometry Unit, Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel. (4)Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. valery.krizhanovsky@weizm
White matter aging drives microglial diversity.

PMID:33606969 2021 Neuron

1. Neuron. 2021 Apr 7;109(7):1100-1117.e10. doi: 10.1016/j.neuron.2021.01.027. Epub 2021 Feb 18. White matter aging drives microglial diversity. Safaiyan S(1), Besson-Girard S(2), Kaya T(3), Cantuti-Castelvetri L(1), Liu L(2), Ji H(2), Schifferer M(4), Gouna G(1), Usifo F(2), Kannaiyan N(5), Fitzner D(6), Xiang X(7), Rossner MJ(5), Brendel M(8), Gokce O(9), Simons M(10). Author information: (1)Institute of Neuronal Cell Biology, Technical University Munich, 80802 Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany. (2)Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, 81377 Munich, Germany. (3)Institute of Neuronal Cell Biology, Technical University Munich, 80802 Munich, Germany; German Center for Neurode
Effects of Fisetin Treatment on Cellular Senescence of Various Tissues and Organs of Old Sheep.

PMID:37627641 2023 Antioxidants (Basel)

1. Antioxidants (Basel). 2023 Aug 21;12(8):1646. doi: 10.3390/antiox12081646. Effects of Fisetin Treatment on Cellular Senescence of Various Tissues and Organs of Old Sheep. Huard CA(1), Gao X(1), Dey Hazra ME(1)(2), Dey Hazra RO(1)(2)(3), Lebsock K(4), Easley JT(4), Millett PJ(1)(2), Huard J(1). Author information: (1)Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA. (2)The Steadman Clinic, Vail, CO 81657, USA. (3)Department for Shoulder and Elbow Surgery, Center for Musculoskeletal Surgery, Charite-University Medicine Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 14195 Berlin, Germany. (4)Preclinical Surgical Research Laboratory, Department of Clinica
Roflumilast Attenuates Microglial Senescence and Retinal Inflammatory Neurodegeneration Post Retinal Ischemia Reperfusion Injury Through Inhibiting NLRP3 Inflammasome.

PMID:39446353 2024 Invest Ophthalmol Vis Sci

1. Invest Ophthalmol Vis Sci. 2024 Oct 1;65(12):38. doi: 10.1167/iovs.65.12.38. Roflumilast Attenuates Microglial Senescence and Retinal Inflammatory Neurodegeneration Post Retinal Ischemia Reperfusion Injury Through Inhibiting NLRP3 Inflammasome. Ou C(1)(2), Lin Y(3), Wen J(4), Zhang H(3), Xu Y(5), Zhang N(3), Liu Q(3), Wu Y(3), Xu J(3), Wu J(1). Author information: (1)Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. (2)Department of General Practice, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong, China. (3)Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. (4)Department of Ophthalmology, Taizhou Central Hospital, T
Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice.

PMID:33470505 2021 Aging Cell

1. Aging Cell. 2021 Feb;20(2):e13296. doi: 10.1111/acel.13296. Epub 2021 Jan 20. Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice. Ogrodnik M(1)(2), Evans SA(3), Fielder E(4), Victorelli S(1), Kruger P(1), Salmonowicz H(1), Weigand BM(1)(2), Patel AD(1), Pirtskhalava T(2), Inman CL(2), Johnson KO(2), Dickinson SL(4), Rocha A(3), Schafer MJ(2), Zhu Y(2), Allison DB(4), von Zglinicki T(5), LeBrasseur NK(2), Tchkonia T(2), Neretti N(3), Passos JF(1)(2), Kirkland JL(1)(2), Jurk D(1)(2). Author information: (1)Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA. (2)Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA. (3)Department of Molecular Biology, Cell Biology and Bi
Cisplatin and methotrexate induce brain microvascular endothelial and microglial senescence in mouse models of chemotherapy-associated cognitive impairment.

PMID:39976845 2025 Geroscience

1. Geroscience. 2025 Jun;47(3):3447-3459. doi: 10.1007/s11357-025-01560-6. Epub 2025 Feb 20. Cisplatin and methotrexate induce brain microvascular endothelial and microglial senescence in mouse models of chemotherapy-associated cognitive impairment. Csik B(#)(1)(2)(3)(4), Vali Kordestan K(#)(1)(2), Gulej R(#)(1)(2)(4), Patai R(1)(2)(3), Nyul-Toth A(1)(2)(3), Shanmugarama S(1)(2)(3), Mukli P(1)(2)(3)(4), Ungvari A(5), Balsara KE(1), McNall RY(6), Razzaghi T(7), Tarantini S(1)(2)(3)(8)(9), Yabluchanskiy A(1)(2)(3)(8)(9), Ungvari Z(1)(2)(3)(8)(9), Csiszar A(1)(2)(6)(10). Author information: (1)Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. (2)Oklahom
Prematurely Aged Human Microglia Exhibit Impaired Stress Response and Defective Nucleocytoplasmic Shuttling of ALS Associated FUS.

PMID:40970514 2025 Aging Cell

1. Aging Cell. 2025 Nov;24(11):e70232. doi: 10.1111/acel.70232. Epub 2025 Sep 19. Prematurely Aged Human Microglia Exhibit Impaired Stress Response and Defective Nucleocytoplasmic Shuttling of ALS Associated FUS. Hartmann C(1), Haß C(1), Knobloch M(1), Barrantes I(2), Fumagalli L(3)(4), Premereur J(3)(4), Markert F(5), Peters M(1), Koromila G(1), Hartmann A(6), Jäger K(6), Abel J(1), Mancuso R(3)(4), Storch A(5)(7)(8), Walter M(6), Fuellen G(2), Hermann A(1)(7)(8). Author information: (1)Translational Neurodegeneration Section "Albrecht Kossel", Department of Neurology, Rostock University Medical Center, Rostock, Germany. (2)Institute for Biostatistics and Informatics in Medicine and Aging Research, Rostock University Medical Center, Rostock, Germany. (3)Department of Biomedical S
Disentangling causality in brain aging: The complex interplay between glial senescence, neuroinflammation, and neurodegeneration.

PMID:41871753 2026 Exp Neurol

1. Exp Neurol. 2026 Mar 21;401:115737. doi: 10.1016/j.expneurol.2026.115737. Online ahead of print. Disentangling causality in brain aging: The complex interplay between glial senescence, neuroinflammation, and neurodegeneration. Suk K(1). Author information: (1)Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; Brain Science & Engineering Institute, Kyungpook National University, Daegu, Republic of Korea; Brain Korea 21 four KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Kyungpook National University, Daegu, Republic of Korea. Electronic address: ksuk@knu.ac.kr. The aging brain is characterized by accumulation of senescent glia, chronic neuroinflammation, and vulnerability to neurode
A tetravalent TREM2 agonistic antibody reduced amyloid pathology in a mouse model of Alzheimer's disease.

PMID:36070367 2022 Sci Transl Med

1. Sci Transl Med. 2022 Sep 7;14(661):eabq0095. doi: 10.1126/scitranslmed.abq0095. Epub 2022 Sep 7. A tetravalent TREM2 agonistic antibody reduced amyloid pathology in a mouse model of Alzheimer's disease. Zhao P(1), Xu Y(2), Jiang L(3), Fan X(1), Li L(1), Li X(1), Arase H(4), Zhao Y(5), Cao W(6), Zheng H(7), Xu H(8)(9), Tong Q(2), Zhang N(1), An Z(1). Author information: (1)Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA. (2)Center for Metabolic and Degenerative Diseases, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA. (3)Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Instit
Adult-onset CNS myelin sulfatide deficiency is sufficient to cause Alzheimer's disease-like neuroinflammation and cognitive impairment.

PMID:34526055 2021 Mol Neurodegener

1. Mol Neurodegener. 2021 Sep 15;16(1):64. doi: 10.1186/s13024-021-00488-7. Adult-onset CNS myelin sulfatide deficiency is sufficient to cause Alzheimer's disease-like neuroinflammation and cognitive impairment. Qiu S(#)(1), Palavicini JP(#)(1)(2), Wang J(1)(3), Gonzalez NS(1), He S(1), Dustin E(4), Zou C(5), Ding L(1)(6), Bhattacharjee A(1), Van Skike CE(1)(7), Galvan V(1)(7), Dupree JL(4)(8), Han X(9)(10). Author information: (1)Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, 4939 Charles Katz Drive, San Antonio, TX, 78229, USA. (2)Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA. (3)Present Address: State Key Lab. of Environmental & Bio
Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic.

PMID:34450028 2021 Cell

1. Cell. 2021 Sep 2;184(18):4651-4668.e25. doi: 10.1016/j.cell.2021.08.002. Epub 2021 Aug 26. Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic. Logan T(1), Simon MJ(1), Rana A(1), Cherf GM(1), Srivastava A(1), Davis SS(1), Low RLY(1), Chiu CL(1), Fang M(1), Huang F(1), Bhalla A(1), Llapashtica C(1), Prorok R(1), Pizzo ME(1), Calvert MEK(1), Sun EW(1), Hsiao-Nakamoto J(1), Rajendra Y(1), Lexa KW(1), Srivastava DB(1), van Lengerich B(1), Wang J(1), Robles-Colmenares Y(1), Kim DJ(1), Duque J(1), Lenser M(1), Earr TK(1), Nguyen H(1), Chau R(1), Tsogtbaatar B(1), Ravi R(1), Skuja LL(1), Solanoy H(1), Rosen HJ(2), Boeve BF(3), Boxer AL(2), Heuer HW(2), Dennis MS(1), Kariolis MS(1), Monroe KM(1), Przybyla L(1), Sanchez PE
CD300f immune receptor contributes to healthy aging by regulating inflammaging, metabolism, and cognitive decline.

PMID:37864797 2023 Cell Rep

1. Cell Rep. 2023 Oct 31;42(10):113269. doi: 10.1016/j.celrep.2023.113269. CD300f immune receptor contributes to healthy aging by regulating inflammaging, metabolism, and cognitive decline. Evans F(1), Alí-Ruiz D(2), Rego N(3), Negro-Demontel ML(1), Lago N(2), Cawen FA(2), Pannunzio B(1), Sanchez-Molina P(4), Reyes L(5), Paolino A(5), Rodríguez-Duarte J(6), Pérez-Torrado V(7), Chicote-González A(8), Quijano C(9), Marmisolle I(9), Mulet AP(10), Schlapp G(10), Meikle MN(10), Bresque M(7), Crispo M(10), Savio E(5), Malagelada C(8), Escande C(7), Peluffo H(11). Author information: (1)Department of Histology and Embryology, Faculty of Medicine, UDELAR, Montevideo, Uruguay; Neuroinflammation and Gene Therapy Laboratory, Institut Pasteur de Montevideo, Montevideo, Uruguay. (2)Neuroinfla
Brain aging mechanisms with mechanical manifestations.

PMID:34600936 2021 Mech Ageing Dev

1. Mech Ageing Dev. 2021 Dec;200:111575. doi: 10.1016/j.mad.2021.111575. Epub 2021 Oct 1. Brain aging mechanisms with mechanical manifestations. Blinkouskaya Y(1), Caçoilo A(1), Gollamudi T(2), Jalalian S(1), Weickenmeier J(3). Author information: (1)Department of Mechanical Engineering, Stevens Institute of Technology, Hoboken, NJ 07030, United States. (2)Department of Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ 07030, United States. (3)Department of Mechanical Engineering, Stevens Institute of Technology, Hoboken, NJ 07030, United States. Electronic address: johannes.weickenmeier@stevens.edu. Brain aging is a complex process that affects everything from the subcellular to the organ level, begins early in life, and accelerates with age. Morphologically
Effect of peripheral cellular senescence on brain aging and cognitive decline.

PMID:36959691 2023 Aging Cell

1. Aging Cell. 2023 May;22(5):e13817. doi: 10.1111/acel.13817. Epub 2023 Mar 23. Effect of peripheral cellular senescence on brain aging and cognitive decline. Budamagunta V(1)(2)(3), Kumar A(1), Rani A(1), Bean L(1), Manohar-Sindhu S(2), Yang Y(3)(4), Zhou D(4), Foster TC(1)(2). Author information: (1)Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, Florida, USA. (2)Genetics and Genomics Graduate Program, Genetics Institute, University of Florida, Gainesville, Florida, USA. (3)Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida, USA. (4)Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA. We examine similar and diff
Microglial senescence.

PMID:24047521 2013 CNS Neurol Disord Drug Targets

1. CNS Neurol Disord Drug Targets. 2013 Sep;12(6):763-7. doi: 10.2174/18715273113126660176. Microglial senescence. Streit WJ(1), Xue QS. Author information: (1)Department of Neuroscience, PO Box 100244, University of Florida, Gainesville, FL 32610-0244, USA. pschorr@ufl.edu. In order to understand microglial senescence it is important to also understand neuroinflammation because the distinction between senescent and activated microglia is a fine one to make and not always made easily. Indeed, it is not easy to reliably identify activated microglia which is why we spend some effort here discussing intricacies associated with both acute and chronic neuroinflammation before addressing the subject of microglial senescence. The idea of microglial senescence in the context of aging-r
TREM2 deficiency delays postnatal microglial maturation and synaptic pruning, leading to anxiety-like behaviors.

PMID:41930604 2026 J Alzheimers Dis
Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy.

PMID:20301376 1993
A scalable human-zebrafish xenotransplantation model reveals gastrosome-mediated processing of dying neurons by human microglia.

PMID:41957412 2026 Commun Biol
Mapping the immune landscape of PCa: From tumor microenvironment to therapeutics.

PMID:41956336 2026 Biochim Biophys Acta Rev Cancer

Evidence against (18)

Microglia-Mediated Neuroinflammation: A Potential Target for the Treatment of Cardiovascular Diseases.

PMID:35642214 2022 J Inflamm Res

Microglia are tissue-resident macrophages of the central nervous system (CNS). In the CNS, microglia play an important role in the monitoring and intervention of synaptic and neuron-level activities. Interventions targeting microglia have been shown to improve the prognosis of various neurological diseases. Recently, studies have observed the activation of microglia in different cardiovascular diseases. In addition, different approaches that regulate the activity of microglia have been shown to
TREM2, microglia, and Alzheimer's disease.

PMID:33516818 2021 Mech Ageing Dev

Triggering receptor expressed on myeloid cells 2 (TREM2) has been suggested to play a crucial role in Alzheimer's disease (AD) pathogenesis, as revealed by genome-wide association studies (GWAS). Since then, rapidly increasing literature related to TREM2 has focused on elucidating its role in AD pathology. In this review, we summarize our understanding of TREM2 biology, explore TREM2 functions in microglia, address the multiple mechanisms of TREM2 in AD, and raise key questions for further inves
Microglia states and nomenclature: A field at its crossroads.

PMID:36327895 2022 Neuron

Microglial research has advanced considerably in recent decades yet has been constrained by a rolling series of dichotomies such as "resting versus activated" and "M1 versus M2." This dualistic classification of good or bad microglia is inconsistent with the wide repertoire of microglial states and functions in development, plasticity, aging, and diseases that were elucidated in recent years. New designations continuously arising in an attempt to describe the different microglial states, notably
TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy.

PMID:29073081 2017 Proc Natl Acad Sci U S A

Variants in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) were recently found to increase the risk for developing Alzheimer's disease (AD). In the brain, TREM2 is predominately expressed on microglia, and its association with AD adds to increasing evidence implicating a role for the innate immune system in AD initiation and progression. Thus far, studies have found
Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology.

PMID:33675684 2021 Neuron

Loss-of-function TREM2 mutations strongly increase Alzheimer's disease (AD) risk. Trem2 deletion has revealed protective Trem2 functions in preclinical models of β-amyloidosis, a prominent feature of pre-diagnosis AD stages. How TREM2 influences later AD stages characterized by tau-mediated neurodegeneration is unclear. To understand Trem2 function in the context of both β-amyloid and tau patholog
SYK coordinates neuroprotective microglial responses in neurodegenerative disease.

PMID:36257314 2022 Cell

Recent studies have begun to reveal critical roles for the brain's professional phagocytes, microglia, and their receptors in the control of neurotoxic amyloid beta (Aβ) and myelin debris accumulation in neurodegenerative disease. However, the critical intracellular molecules that orchestrate neuroprotective functions of microglia remain poorly understood. In our studies, we find that targeted del
Cognitive enhancement and neuroprotective effects of OABL, a sesquiterpene lactone in 5xFAD Alzheimer's disease mice model.

PMID:35026701 2022 Redox Biol

Alzheimer's disease (AD) is a neurodegenerative disease in which oxidative stress and neuroinflammation were demonstrated to be associated with neuronal loss and cognitive deficits. However, there are still no specific treatments that can prevent the progression of AD. In this study, a screening of anti-inflammatory hits from 4207 natural compounds of two different molecular libraries indicated 1,
Glial reactivity correlates with synaptic dysfunction across aging and Alzheimer's disease.

PMID:40593718 2025 Nat Commun

Previous studies suggest glial and neuronal changes may trigger synaptic dysfunction in Alzheimer's disease (AD), but the link between their markers and synaptic abnormalities in the living brain remains unclear. We investigated the association between glial reactivity and synaptic dysfunction biomarkers in cerebrospinal fluid (CSF) from 478 individuals in cognitively unimpaired (CU) and cognitive
Sulfatide deficiency-induced astrogliosis and myelin lipid dyshomeostasis are independent of TREM2-mediated microglial activation.

PMID:41513633 2026 Nat Commun

Disrupted lipid homeostasis and neuroinflammation often co-exist in neurodegenerative disorders, including Alzheimer's disease (AD). However, the intrinsic connection and causal relationship between these deficits remain elusive. Our previous studies show that the loss of sulfatide (ST), a class of myelin-enriched lipids, causes AD-like neuroinflammatory responses, cognitive impairment, bladder en
cGAS-STING drives ageing-related inflammation and neurodegeneration.

PMID:37532932 2023 Nature

Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease
Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes.

PMID:30471926 2019 Immunity

Microglia, the resident immune cells of the brain, rapidly change states in response to their environment, but we lack molecular and functional signatures of different microglial populations. Here, we analyzed the RNA expression patterns of more than 76,000 individual microglia in mice during development, in old age, and after brain injury. Our analysis uncovered at least nine transcriptionally di
Lectins and neurodegeneration: A glycobiologist's perspective.

PMID:40405515 2025 Adv Clin Exp Med

1. Adv Clin Exp Med. 2025 May;34(5):673-679. doi: 10.17219/acem/204107. Lectins and neurodegeneration: A glycobiologist's perspective. Olejnik B(1), Ferens-Sieczkowska M(1). Author information: (1)Department of Biochemistry and Immunochemistry, Wroclaw Medical University, Poland. Neurodegenerative diseases, including Alzheimer's and Parkinson's disease, affect an increasing number of people in aging societies, dramatically reducing the quality of life of those affected. Hence, intensive research efforts are aimed at understanding the molecular mechanisms of the disease progress, with the hope for developing effective therapeutic strategies. The progress of neurodegenerative diseases is associated with a complex activity of the immune system in the brain tissue. Carbohydrate-bind
Effect of aging on biomarkers and clinical profile in Parkinson's disease.

PMID:40991070 2025 J Neurol

1. J Neurol. 2025 Sep 24;272(10):651. doi: 10.1007/s00415-025-13384-7. Effect of aging on biomarkers and clinical profile in Parkinson's disease. Di Lazzaro G(1)(2), Paolini Paoletti F(3), Bellomo G(3), Schirinzi T(4), Grillo P(5)(6), Giuffrè GM(7)(8), Petracca M(7)(8), Picca A(7)(9), Mercuri NB(4), Parnetti L(3), Calabresi P(7)(8), Bentivoglio AR(7)(8). Author information: (1)Neurology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Agostino Gemelli 8, 00168, Rome, Italy. giulia.dilazzaro@policlinicogemelli.it. (2)Università Cattolica del Sacro Cuore, Rome, Italy. giulia.dilazzaro@policlinicogemelli.it. (3)Section of Neurology, Department of Medicine and Surgery, University Hospital of Perugia, Perugia, Italy. (4)Neurology Unit, Department of Systems Medi
Regulation of TREM2 expression by transcription factor YY1 and its protective effect against Alzheimer's disease.

PMID:37044212 2023 J Biol Chem

1. J Biol Chem. 2023 May;299(5):104688. doi: 10.1016/j.jbc.2023.104688. Epub 2023 Apr 11. Regulation of TREM2 expression by transcription factor YY1 and its protective effect against Alzheimer's disease. Lu Y(1), Huang X(1), Liang W(1), Li Y(1), Xing M(2), Pan W(2), Zhang Y(1), Wang Z(3), Song W(4). Author information: (1)The National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical University, Beijing, China. (2)Zhejiang Provincial Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Wenzhou Kangning Hospital, Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Wenzhou Medical University, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou,
Microglia in Brain Aging and Age-Related Diseases: Friends or Foes?

PMID:41373648 2025 Int J Mol Sci

1. Int J Mol Sci. 2025 Nov 27;26(23):11494. doi: 10.3390/ijms262311494. Microglia in Brain Aging and Age-Related Diseases: Friends or Foes? Ishikawa K(1), Fujikawa R(1), Okita K(1), Kimura F(1), Watanabe T(1), Katsurabayashi S(1), Iwasaki K(1). Author information: (1)Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. With the global rise in population aging, establishing effective strategies for the prevention and treatment of age-related neurodegenerative diseases, as well as their prodromal stage of cognitive frailty, has become an urgent challenge. Recent studies have revealed that the neural basis of both frailty and age-related disorders is closely associated with chronic neuroinflammat
Rejuvenating aged microglia by p16(ink4a)-siRNA-loaded nanoparticles increases amyloid-β clearance in animal models of Alzheimer's disease.

PMID:38493185 2024 Mol Neurodegener

1. Mol Neurodegener. 2024 Mar 16;19(1):25. doi: 10.1186/s13024-024-00715-x. Rejuvenating aged microglia by p16(ink4a)-siRNA-loaded nanoparticles increases amyloid-β clearance in animal models of Alzheimer's disease. Shin HJ(1)(2), Kim IS(3)(4), Choi SG(1)(2), Lee K(1)(3)(5), Park H(1)(3), Shin J(1)(3), Kim D(1), Beom J(5), Yi YY(6), Gupta DP(7), Song GJ(7)(8), Chung WS(9), Lee CJ(10)(11), Kim DW(12)(13)(14)(15). Author information: (1)Department of Anatomy and Cell Biology, Chungnam National University College of Medicine, Daejeon, Republic of Korea. (2)Brain Research Institute, Chungnam National University College of Medicine, Daejeon, Republic of Korea. (3)Department of Medical Science, Chungnam National University College of Medicine, Daejeon, Republic of Korea. (4)Department o
Microglial Replacement Reverses Age-Associated Epigenetic Modifications Despite Accelerating Epigenetic Age.

PMID:41135104 2025 Aging Dis

1. Aging Dis. 2025 Oct 22. doi: 10.14336/AD.2025.1066. Online ahead of print. Microglial Replacement Reverses Age-Associated Epigenetic Modifications Despite Accelerating Epigenetic Age. Arbaizar-Rovirosa M(1)(2), Pérez RF(3), Peñarroya A(4)(5)(6)(7), Gallizioli M(1), Fraga MF(8)(4)(5)(9)(10), Planas AM(1)(2). Author information: (1)Cerebrovascular Research Laboratory, Instituto de Investigaciones. (2)Biomédicas de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. (3)Departamento de Bioquímica y Biología Molecular, Facultad de Veterinaria, Universidad Complutense de Madrid, Madrid, Spain. (4)Cancer Epigenetics and Nanomedicine Laboratory, Centro de Investi
Microglial aging in the healthy CNS: phenotypes, drivers, and rejuvenation.

PMID:23493481 2013 Front Cell Neurosci

1. Front Cell Neurosci. 2013 Mar 13;7:22. doi: 10.3389/fncel.2013.00022. eCollection 2013. Microglial aging in the healthy CNS: phenotypes, drivers, and rejuvenation. Wong WT(1). Author information: (1)Unit on Neuron-Glia Interactions in Retinal Disease, National Eye Institute, National Institutes of Health Bethesda, MD, USA. Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and age-related macular degeneration (AMD), share two characteristics in common: (1) a disease prevalence that increases markedly with advancing age, and (2) neuroinflammatory changes in which microglia, the primary resident immune cell of the CNS, feature prominently. These characteristics have led to the hypothesis that pathogenic mechanisms underlying age-related neurodegenerati

Evidence matrix

35 supporting 18 contradicting

33% posterior support

Supporting

Sleep deprivation exacerbates microglial reactivity and Aβ deposition in a TREM2-dependent manner in mice. PMID:37099634 · 2023 · Sci Transl Med
Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease. PMID:31932797 · 2020 · Nat Med
TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways. PMID:36306735 · 2022 · Cell
TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease. PMID:28802038 · 2017 · Cell
Explores genetic variations linked to neurodegenerative disease proteins, potentially supporting the TREM2-dependent senescence hypothesis. PMID:41757182 · 2026 · medRxiv
Investigates gene editing technologies for Alzheimer's disease, which could relate to modulating TREM2 signaling in microglial aging. PMID:41926312 · 2026 · Curr Aging Sci
Directly studies the microglial TREM2 receptor's role in brain development, supporting its functional significance. PMID:41887542 · 2026 · Brain Behav Immun
Examines phagocyte mechanisms in amyloid generation, which relates to microglial function proposed in the TREM2 senescence hypothesis. PMID:41770935 · 2026 · Proc Natl Acad Sci U S A
Explores microglial neuroprotective responses, which aligns with TREM2 signaling mechanisms. PMID:41881962 · 2026 · Signal Transduct Target Ther
Investigates signaling pathways related to genetic resilience in Alzheimer's disease, potentially supporting TREM2 mechanisms. PMID:41888907 · 2026 · Mol Neurodegener
Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model. PMID:39353433 · 2024 · Neuron
Microglia in neurodegeneration. PMID:30258234 · 2018 · Nat Neurosci
TREM2 receptor protects against complement-mediated synaptic loss by binding to complement C1q during neurodegeneration. PMID:37442133 · 2023 · Immunity
TREM2 and sTREM2 in Alzheimer's disease: from mechanisms to therapies. PMID:40247363 · 2025 · Mol Neurodegener
Soluble TREM2 ameliorates tau phosphorylation and cognitive deficits through activating transgelin-2 in Alzheimer's disease. PMID:37865646 · 2023 · Nat Commun
Preclinical and first-in-human evaluation of AL002, a novel TREM2 agonistic antibody for Alzheimer's disease. PMID:39444037 · 2024 · Alzheimers Res Ther
Identification of senescent, TREM2-expressing microglia in aging and Alzheimer's disease model mouse brain. PMID:38637622 · 2024 · Nat Neurosci
White matter aging drives microglial diversity. PMID:33606969 · 2021 · Neuron
Effects of Fisetin Treatment on Cellular Senescence of Various Tissues and Organs of Old Sheep. PMID:37627641 · 2023 · Antioxidants (Basel)
Roflumilast Attenuates Microglial Senescence and Retinal Inflammatory Neurodegeneration Post Retinal Ischemia Reperfusion Injury Through Inhibiting NLRP3 Inflammasome. PMID:39446353 · 2024 · Invest Ophthalmol Vis Sci
Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice. PMID:33470505 · 2021 · Aging Cell
Cisplatin and methotrexate induce brain microvascular endothelial and microglial senescence in mouse models of chemotherapy-associated cognitive impairment. PMID:39976845 · 2025 · Geroscience
Prematurely Aged Human Microglia Exhibit Impaired Stress Response and Defective Nucleocytoplasmic Shuttling of ALS Associated FUS. PMID:40970514 · 2025 · Aging Cell
Disentangling causality in brain aging: The complex interplay between glial senescence, neuroinflammation, and neurodegeneration. PMID:41871753 · 2026 · Exp Neurol
A tetravalent TREM2 agonistic antibody reduced amyloid pathology in a mouse model of Alzheimer's disease. PMID:36070367 · 2022 · Sci Transl Med
Adult-onset CNS myelin sulfatide deficiency is sufficient to cause Alzheimer's disease-like neuroinflammation and cognitive impairment. PMID:34526055 · 2021 · Mol Neurodegener
Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic. PMID:34450028 · 2021 · Cell
CD300f immune receptor contributes to healthy aging by regulating inflammaging, metabolism, and cognitive decline. PMID:37864797 · 2023 · Cell Rep
Brain aging mechanisms with mechanical manifestations. PMID:34600936 · 2021 · Mech Ageing Dev
Effect of peripheral cellular senescence on brain aging and cognitive decline. PMID:36959691 · 2023 · Aging Cell
Microglial senescence. PMID:24047521 · 2013 · CNS Neurol Disord Drug Targets
TREM2 deficiency delays postnatal microglial maturation and synaptic pruning, leading to anxiety-like behaviors. PMID:41930604 · 2026 · J Alzheimers Dis
Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy. PMID:20301376 · 1993
A scalable human-zebrafish xenotransplantation model reveals gastrosome-mediated processing of dying neurons by human microglia. PMID:41957412 · 2026 · Commun Biol
Mapping the immune landscape of PCa: From tumor microenvironment to therapeutics. PMID:41956336 · 2026 · Biochim Biophys Acta Rev Cancer

Contradicting

Microglia-Mediated Neuroinflammation: A Potential Target for the Treatment of Cardiovascular Diseases. PMID:35642214 · 2022 · J Inflamm Res
TREM2, microglia, and Alzheimer's disease. PMID:33516818 · 2021 · Mech Ageing Dev
Microglia states and nomenclature: A field at its crossroads. PMID:36327895 · 2022 · Neuron
TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. PMID:29073081 · 2017 · Proc Natl Acad Sci U S A
Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology. PMID:33675684 · 2021 · Neuron
SYK coordinates neuroprotective microglial responses in neurodegenerative disease. PMID:36257314 · 2022 · Cell
Cognitive enhancement and neuroprotective effects of OABL, a sesquiterpene lactone in 5xFAD Alzheimer's disease mice model. PMID:35026701 · 2022 · Redox Biol
Glial reactivity correlates with synaptic dysfunction across aging and Alzheimer's disease. PMID:40593718 · 2025 · Nat Commun
Sulfatide deficiency-induced astrogliosis and myelin lipid dyshomeostasis are independent of TREM2-mediated microglial activation. PMID:41513633 · 2026 · Nat Commun
cGAS-STING drives ageing-related inflammation and neurodegeneration. PMID:37532932 · 2023 · Nature
Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes. PMID:30471926 · 2019 · Immunity
Lectins and neurodegeneration: A glycobiologist's perspective. PMID:40405515 · 2025 · Adv Clin Exp Med
Effect of aging on biomarkers and clinical profile in Parkinson's disease. PMID:40991070 · 2025 · J Neurol
Regulation of TREM2 expression by transcription factor YY1 and its protective effect against Alzheimer's disease. PMID:37044212 · 2023 · J Biol Chem
Microglia in Brain Aging and Age-Related Diseases: Friends or Foes? PMID:41373648 · 2025 · Int J Mol Sci
Rejuvenating aged microglia by p16(ink4a)-siRNA-loaded nanoparticles increases amyloid-β clearance in animal models of Alzheimer's disease. PMID:38493185 · 2024 · Mol Neurodegener
Microglial Replacement Reverses Age-Associated Epigenetic Modifications Despite Accelerating Epigenetic Age. PMID:41135104 · 2025 · Aging Dis
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Top-ranked evidence

trust_score × relevance_score × exp(-recency_weight × recency_days / 365)

Supports · top 3

#1 paper-20301376 0.233 trust 0.50 · rel 0.50 · 84d
#2 paper-41957412 0.233 trust 0.50 · rel 0.50 · 84d
#3 paper-41956336 0.233 trust 0.50 · rel 0.50 · 84d

3 total ranked · scidex.hypotheses.evidence_ranking

Bayesian persona consensus

33% posterior support

12 signals · 4 for / 8 against · agreement 33%

scidex.consensus.bayesian compounds vote / rank / fund signals from 12 contributing personas in log-odds space, weighted by uniform. Prior 50%.

Cite this hypothesis

Citation

etl-backfill (2026). TREM2-Mediated Astrocyte-Microglia Crosstalk in Neurodegeneration. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/h-var-66156774e7

BibTeX

@misc{scidex_hypothesis_hvar6615,
  title        = {TREM2-Mediated Astrocyte-Microglia Crosstalk in Neurodegeneration},
  author       = {etl-backfill},
  year         = {2026},
  howpublished = {SciDEX hypothesis},
  url          = {https://prism.scidex.ai/hypotheses/h-var-66156774e7},
  note         = {SciDEX artifact hypothesis:h-var-66156774e7}
}

kind	normalized	weight
calibration	0.000	1.50
vote	0.286	1.00

Mechanistic description