TREM2-CSF1R Cross-Talk in Microglial Metabolic Reprogramming

The TREM2-CSF1R metabolic cross-talk hypothesis centers on the intricate molecular interactions between triggering receptor expressed on myeloid cells 2 (TREM2) and colony-stimulating factor 1 receptor (CSF1R) signaling cascades that collectively orchestrate microglial metabolic homeostasis. TREM2, a transmembrane glycoprotein predominantly expressed on microglia, functions as a pattern recognition receptor that binds diverse ligands including phospholipids, lipoproteins, and amyloid-β oligomers through its immunoglobulin-like domain. Upon ligand engagement, TREM2 associates with the adaptor protein DAP12 (DNAX activation protein 12), which contains immunoreceptor tyrosine-based activation motifs (ITAMs). This interaction triggers phosphorylation of DAP12 by Src family kinases, subsequently recruiting and activating spleen tyrosine kinase (SYK). Activated SYK initiates multiple downstream signaling cascades, including phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and phospholipase C gamma (PLCγ) pathways.

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Molecular Mechanism and Rationale

The TREM2-CSF1R metabolic cross-talk hypothesis centers on the intricate molecular interactions between triggering receptor expressed on myeloid cells 2 (TREM2) and colony-stimulating factor 1 receptor (CSF1R) signaling cascades that collectively orchestrate microglial metabolic homeostasis. TREM2, a transmembrane glycoprotein predominantly expressed on microglia, functions as a pattern recognition receptor that binds diverse ligands including phospholipids, lipoproteins, and amyloid-β oligomers through its immunoglobulin-like domain. Upon ligand engagement, TREM2 associates with the adaptor protein DAP12 (DNAX activation protein 12), which contains immunoreceptor tyrosine-based activation motifs (ITAMs). This interaction triggers phosphorylation of DAP12 by Src family kinases, subsequently recruiting and activating spleen tyrosine kinase (SYK). Activated SYK initiates multiple downstream signaling cascades, including phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and phospholipase C gamma (PLCγ) pathways.

Concurrently, CSF1R, a receptor tyrosine kinase essential for microglial survival and proliferation, responds to its ligands colony-stimulating factor 1 (CSF1) and interleukin-34 (IL-34). CSF1R dimerization and autophosphorylation create docking sites for multiple signaling proteins, activating PI3K/AKT, mitogen-activated protein kinase (MAPK), and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways. The convergence of TREM2 and CSF1R signaling occurs at multiple nodes, particularly through shared activation of PI3K/AKT pathways and downstream metabolic regulators.

Under homeostatic conditions, this cross-talk promotes oxidative metabolism by activating peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the master regulator of mitochondrial biogenesis. Both TREM2 and CSF1R signaling converge on mechanistic target of rapamycin complex 1 (mTORC1), which integrates nutrient and energy signals to coordinate anabolic processes. The balanced activation promotes fatty acid oxidation through carnitine palmitoyltransferase 1A (CPT1A) upregulation and enhances tricarboxylic acid (TCA) cycle flux. This metabolic programming supports ATP-dependent processes crucial for phagocytosis, including phagosome formation, lysosomal fusion, and debris processing. Additionally, the TREM2-CSF1R axis regulates cholesterol homeostasis through sterol regulatory element-binding protein 2 (SREBP2) and liver X receptor (LXR) signaling, maintaining lipid membrane integrity essential for phagocytic function.

Preclinical Evidence

Compelling preclinical evidence supporting the TREM2-CSF1R metabolic cross-talk hypothesis has emerged from multiple experimental systems. In 5xFAD transgenic mice, a well-established model of amyloid pathology expressing human APP and PSEN1 mutations, TREM2 knockout results in profound alterations in microglial metabolism. Single-cell RNA sequencing studies have demonstrated that TREM2-deficient microglia exhibit a 70-85% reduction in oxidative phosphorylation gene expression, including significant downregulation of cytochrome c oxidase subunits and ATP synthase components. Metabolomic analyses using liquid chromatography-mass spectrometry reveal a 40-60% decrease in TCA cycle intermediates, including citrate, α-ketoglutarate, and succinate, in TREM2-knockout microglia compared to wild-type controls.

Seahorse extracellular flux analyses of primary microglial cultures have provided quantitative evidence of metabolic dysfunction. TREM2-deficient microglia demonstrate a 50-65% reduction in oxygen consumption rate (OCR) and a compensatory 3-4 fold increase in extracellular acidification rate (EACR), indicating a pathological shift toward glycolysis. This metabolic reprogramming is accompanied by impaired phagocytic capacity, with TREM2-knockout microglia showing 60-75% reduced uptake of fluorescent amyloid-β fibrils and 45-55% decreased clearance of apoptotic neurons in vitro.

CSF1R inhibition studies using PLX3397 and PLX5622 in APP/PS1 mice have revealed complementary findings. Pharmacological CSF1R blockade results in 90-95% microglial depletion within 7-14 days, followed by rapid repopulation upon drug withdrawal. During the repopulation phase, newly generated microglia exhibit altered metabolic profiles characterized by increased glycolytic gene expression and reduced mitochondrial content, as measured by MitoTracker staining and transmission electron microscopy. These metabolically immature microglia demonstrate compromised phagocytic function and fail to effectively cluster around amyloid plaques.

Caenorhabditis elegans models expressing human amyloid-β have provided additional mechanistic insights. Loss-of-function mutations in ced-1, the C. elegans TREM2 ortholog, combined with reduced expression of csf-1r homologs, result in accelerated protein aggregate accumulation and shortened lifespan. Metabolic profiling using mass spectrometry reveals disrupted fatty acid oxidation and impaired autophagy flux, consistent with observations in mammalian systems.

Therapeutic Strategy and Delivery

The therapeutic approach targeting TREM2-CSF1R metabolic cross-talk encompasses multiple modalities designed to restore microglial metabolic homeostasis and enhance phagocytic function. The primary strategy involves developing dual-specificity small molecules that simultaneously modulate both TREM2 and CSF1R signaling pathways. Lead compounds identified through high-throughput screening include novel benzimidazole derivatives that act as positive allosteric modulators of TREM2 while enhancing CSF1R sensitivity to endogenous ligands.

AL002c, a humanized monoclonal antibody targeting TREM2, represents an alternative therapeutic approach currently in clinical development. This antibody functions as a receptor agonist, enhancing TREM2 clustering and downstream signaling without requiring endogenous ligand binding. Preclinical pharmacokinetic studies demonstrate that AL002c crosses the blood-brain barrier with approximately 0.1-0.3% brain penetration following intravenous administration, achieving therapeutically relevant concentrations in brain tissue. The recommended dosing regimen involves monthly intravenous infusions of 20-60 mg/kg, based on dose-escalation studies in non-human primates.

Gene therapy approaches utilizing adeno-associated virus (AAV) vectors offer potential advantages for sustained therapeutic delivery. AAV-PHP.eB vectors engineered to express enhanced TREM2 variants or CSF1R modulatory proteins demonstrate superior brain tropism and microglial transduction efficiency. Intrathecal delivery of 1×10^12 vector genomes achieves widespread microglial transduction with minimal systemic exposure, reducing potential off-target effects on peripheral macrophages.

Pharmacokinetic considerations include the need for sustained receptor engagement to achieve metabolic reprogramming. Small molecule approaches require twice-daily oral dosing to maintain therapeutic concentrations, with plasma half-lives of 8-12 hours for lead compounds. Antibody therapies benefit from extended half-lives of 14-21 days in cerebrospinal fluid, enabling monthly dosing schedules. Combination approaches pairing TREM2 agonists with CSF1R modulators may provide synergistic effects while allowing dose reduction to minimize potential adverse effects.

Evidence for Disease Modification

Distinguishing disease-modifying effects from symptomatic improvements requires comprehensive biomarker assessment and longitudinal monitoring of pathological progression. The most compelling evidence for disease modification comes from quantitative amyloid and tau imaging studies combined with cerebrospinal fluid (CSF) biomarker analyses. In 5xFAD mice treated with TREM2-CSF1R pathway modulators, methoxy-X04 amyloid imaging reveals 35-50% reductions in cortical and hippocampal plaque burden compared to vehicle-treated controls after 12 weeks of treatment. Importantly, these improvements are accompanied by corresponding decreases in CSF amyloid-β42/40 ratios and increases in soluble TREM2 (sTREM2) levels, indicating enhanced microglial activation and plaque clearance.

Tau pathology assessment using AT8 immunostaining in rTg4510 tau transgenic mice demonstrates 40-55% reductions in phosphorylated tau accumulation following combination TREM2-CSF1R therapy. CSF phospho-tau181 and phospho-tau217 levels, established biomarkers of tau pathology, show corresponding decreases of 25-40% in treated animals. Neurofilament light chain (NfL), a sensitive marker of axonal damage, exhibits 60-70% reductions in both CSF and plasma, suggesting neuroprotective effects beyond aggregate clearance.

Functional outcomes provide additional evidence of disease modification rather than symptomatic treatment. Novel object recognition testing reveals sustained cognitive improvements that persist beyond the treatment period, indicating lasting neuroprotective effects. Electrophysiological recordings demonstrate restoration of long-term potentiation (LTP) in hippocampal slices from treated animals, with synaptic strength improvements of 80-120% compared to baseline. These functional improvements correlate with increased dendritic spine density and synaptic protein expression, measured using high-resolution microscopy and Western blotting.

Neuroinflammation biomarkers provide mechanistic evidence of disease modification. Positron emission tomography (PET) imaging using the translocator protein (TSPO) tracer [11C]PK11195 shows normalized microglial activation patterns in treated animals, with standardized uptake values returning to levels observed in wild-type controls. Multiplex cytokine analyses reveal rebalanced inflammatory profiles, with decreased pro-inflammatory markers (TNF-α, IL-1β, IL-6) and increased anti-inflammatory mediators (IL-10, TGF-β).

Clinical Translation Considerations

Successful clinical translation of TREM2-CSF1R metabolic reprogramming therapies requires careful patient stratification and biomarker-driven trial design. Genetic screening for TREM2 risk variants, including R47H, R62H, and rare loss-of-function mutations, will identify patients most likely to benefit from intervention. Approximately 2-4% of late-onset Alzheimer's disease patients carry pathogenic TREM2 variants, representing a defined population for precision medicine approaches. Additionally, CSF sTREM2 levels serve as pharmacodynamic biomarkers for treatment response, with baseline levels below 2,000 pg/mL indicating potential therapeutic candidates.

Phase I safety trials will focus on establishing maximum tolerated doses and identifying dose-limiting toxicities. Key safety considerations include potential immune activation, given the central role of TREM2 and CSF1R in myeloid cell function. Comprehensive monitoring of peripheral blood cell counts, particularly monocyte and neutrophil populations, will detect any systemic immune perturbations. Liver function tests and inflammatory markers require regular assessment, as CSF1R modulation may affect hepatic Kupffer cell function.

Regulatory pathways will likely follow the FDA's accelerated approval process, utilizing biomarker endpoints for initial approval followed by confirmatory clinical outcome studies. The recent approval of aducanumab based on amyloid reduction provides precedent for biomarker-driven approvals in Alzheimer's disease. Primary endpoints will include CSF amyloid-β42/40 ratios and tau biomarkers, with amyloid PET imaging as supportive evidence.

The competitive landscape includes other microglial-targeting therapies currently in development. Sanofi's SAR442168 (TREM2 agonist) and Denali Therapeutics' DNL593 (RIPK1 inhibitor targeting microglial activation) represent direct competitors. Differentiation will focus on the unique metabolic reprogramming approach and potential for combination therapy with existing anti-amyloid treatments.

Future Directions and Combination Approaches

The TREM2-CSF1R metabolic axis represents a foundational platform for developing comprehensive neurodegeneration therapeutics extending beyond Alzheimer's disease. Future research directions include investigating this pathway in frontotemporal dementia, Parkinson's disease, and amyotrophic lateral sclerosis, where microglial dysfunction contributes to pathogenesis. Single-cell genomics studies across these conditions reveal shared metabolic signatures suggesting broad therapeutic applicability.

Combination approaches with existing Alzheimer's treatments offer synergistic potential. Pairing TREM2-CSF1R modulators with anti-amyloid monoclonal antibodies (aducanumab, lecanemab) may enhance plaque clearance while reducing inflammation-related adverse events such as amyloid-related imaging abnormalities (ARIA). Preclinical studies combining metabolic modulators with gamma-secretase modulators show enhanced cognitive outcomes compared to monotherapy approaches.

Emerging therapeutic targets within the metabolic pathway provide additional combination opportunities. Sirtuin 1 (SIRT1) activators enhance mitochondrial function and complement TREM2-CSF1R metabolic programming. Nicotinamide adenine dinucleotide (NAD+) precursors, including nicotinamide riboside and nicotinamide mononucleotide, synergistically improve microglial energetics and may enhance therapeutic efficacy.

Advanced delivery technologies, including focused ultrasound-mediated blood-brain barrier opening and engineered extracellular vesicles, offer improved CNS penetration for therapeutic molecules. Bioengineered microglia derived from induced pluripotent stem cells provide potential cell replacement strategies for patients with severe microglial dysfunction. Integration of artificial intelligence and machine learning approaches will optimize dosing regimens and predict treatment responses based on multimodal biomarker profiles, personalizing therapy for individual patients and maximizing therapeutic benefit while minimizing adverse effects.

🧬 Mechanism

🧬 Curated Mechanism Pathway

Curated pathway from expert analysis

flowchart TD
    subgraph Genetics["Genetic Risk"]
        A1["TREM2 R47H Variant<br/>3x AD Risk"] --> A2["Impaired Ligand Binding<br/>(Abeta, ApoE, PS)"]
        A3["TREM2 R62H Variant<br/>2x AD Risk"] --> A4["Reduced Surface Expression"]
        A5["TREM2 H157Y<br/>Increased Shedding"] --> A6["Elevated sTREM2"]
    end

    subgraph Signaling["TREM2 Signaling Cascade"]
        B1["TREM2 + DAP12/TYROBP"] --> B2["ITAM Phosphorylation"]
        B2 --> B3["SYK Kinase Activation"]
        B3 --> B4["PI3K/AKT Pathway"]
        B3 --> B5["PLCgamma2/Ca2+ Flux"]
        B4 --> B6["mTOR -> Metabolic Reprogramming"]
        B4 --> B7["NF-kappaB Modulation"]
        B5 --> B8["NFAT Translocation"]
    end

    subgraph Microglial["Microglial States"]
        C1["Homeostatic Microglia<br/>(P2RY12+, CX3CR1+)"]
        C2["Disease-Associated Microglia<br/>(DAM Stage 1)"]
        C3["DAM Stage 2<br/>(TREM2-dependent)"]
        C4["Senescent Microglia<br/>(p16+, p21+, SA-beta-gal+)"]
        C1 -->|"Abeta sensing"| C2
        C2 -->|"TREM2 signal"| C3
        C2 -->|"chronic stress"| C4
    end

    subgraph Senescence["Senescence Program"]
        D1["DNA Damage Response<br/>(ATM/ATR)"] --> D2["p53 Stabilization"]
        D2 --> D3["p21/CDKN1A Upregulation"]
        D3 --> D4["Cell Cycle Arrest"]
        D4 --> D5["SASP Activation"]
        D5 --> D6["IL-6, IL-1beta, TNF-alpha<br/>MMP3, MMP9"]
        D5 --> D7["Extracellular Vesicles<br/>(pro-inflammatory cargo)"]
    end

    subgraph Pathology["Downstream Pathology"]
        E1["Impaired Abeta Clearance"]
        E2["Tau Propagation"]
        E3["Synaptic Loss"]
        E4["BBB Dysfunction"]
        E1 --> E5["Plaque Accumulation"]
        E2 --> E6["Tangle Formation"]
        E3 --> E7["Cognitive Decline"]
        E4 --> E7
        E5 --> E7
        E6 --> E7
    end

    subgraph Therapy["Therapeutic Strategy"]
        F1["TREM2 Agonist Antibodies<br/>(AL002/Latozinemab)"]
        F2["Senolytic Drugs<br/>(Dasatinib + Quercetin)"]
        F3["SASP Inhibitors<br/>(Rapamycin, Ruxolitinib)"]
    end

    A2 --> B1
    A4 --> B1
    B6 --> C3
    C3 -->|"sustained activation"| D1
    C4 --> D5
    D6 --> E1
    D6 --> E2
    D6 --> E3
    D6 --> E4

    F1 -.->|"restore"| B1
    F1 -.->|"promote"| C3
    F2 -.->|"clear"| C4
    F3 -.->|"block"| D5

    style A1 fill:#ce93d8,color:#000
    style A3 fill:#ce93d8,color:#000
    style A5 fill:#ce93d8,color:#000
    style C3 fill:#4fc3f7,color:#000
    style C4 fill:#ffd54f,color:#000
    style D5 fill:#ff8a65,color:#000
    style E7 fill:#ef5350,color:#fff
    style F1 fill:#81c784,color:#000
    style F2 fill:#81c784,color:#000
    style F3 fill:#81c784,color:#000

⚖️ Evidence

⚖️ Evidence Matrix36 supports18 contradicts

Supports

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

Sci Transl Med2023PMID:37099634medium

Abstract

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

Supports

Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease.

Nat Med2020PMID:31932797medium

Abstract

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

Supports

TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways.

Cell2022PMID:36306735medium

Abstract

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

Supports

TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease.

Cell2017PMID:28802038medium

Abstract

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-

Supports

Explores genetic variations linked to neurodegenerative disease proteins, potentially supporting the TREM2-dependent senescence hypothesis.

medRxiv2026PMID:41757182

Supports

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

Curr Aging Sci2026PMID:41926312

Supports

Directly studies the microglial TREM2 receptor's role in brain development, supporting its functional significance.

Brain Behav Immun2026PMID:41887542

Supports

Examines phagocyte mechanisms in amyloid generation, which relates to microglial function proposed in the TREM2 senescence hypothesis.

Proc Natl Acad Sci U S A2026PMID:41770935

Supports

Explores microglial neuroprotective responses, which aligns with TREM2 signaling mechanisms.

Signal Transduct Target Ther2026PMID:41881962

Supports

Investigates signaling pathways related to genetic resilience in Alzheimer's disease, potentially supporting TREM2 mechanisms.

Mol Neurodegener2026PMID:41888907

Supports

Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model.

Neuron2024PMID:39353433high

Abstract

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

Supports

Microglia in neurodegeneration.

Nat Neurosci2018PMID:30258234high

Abstract

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

Supports

TREM2 receptor protects against complement-mediated synaptic loss by binding to complement C1q during neurodegeneration.

Immunity2023PMID:37442133medium

Abstract

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

Supports

TREM2 and sTREM2 in Alzheimer's disease: from mechanisms to therapies.

Mol Neurodegener2025PMID:40247363medium

Abstract

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

Supports

Soluble TREM2 ameliorates tau phosphorylation and cognitive deficits through activating transgelin-2 in Alzheimer's disease.

Nat Commun2023PMID:37865646medium

Abstract

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

Supports

Preclinical and first-in-human evaluation of AL002, a novel TREM2 agonistic antibody for Alzheimer's disease.

Alzheimers Res Ther2024PMID:39444037medium

Abstract

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

Supports

Identification of senescent, TREM2-expressing microglia in aging and Alzheimer's disease model mouse brain.

Nat Neurosci2024PMID:38637622high

Abstract

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

Supports

White matter aging drives microglial diversity.

Neuron2021PMID:33606969medium

Abstract

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

Supports

Effects of Fisetin Treatment on Cellular Senescence of Various Tissues and Organs of Old Sheep.

Antioxidants (Basel)2023PMID:37627641high

Abstract

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

Supports

Roflumilast Attenuates Microglial Senescence and Retinal Inflammatory Neurodegeneration Post Retinal Ischemia Reperfusion Injury Through Inhibiting NLRP3 Inflammasome.

Invest Ophthalmol Vis Sci2024PMID:39446353high

Abstract

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

Supports

Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice.

Aging Cell2021PMID:33470505high

Abstract

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

Supports

Cisplatin and methotrexate induce brain microvascular endothelial and microglial senescence in mouse models of chemotherapy-associated cognitive impairment.

Geroscience2025PMID:39976845high

Abstract

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

Supports

Prematurely Aged Human Microglia Exhibit Impaired Stress Response and Defective Nucleocytoplasmic Shuttling of ALS Associated FUS.

Aging Cell2025PMID:40970514medium

Abstract

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

Supports

Disentangling causality in brain aging: The complex interplay between glial senescence, neuroinflammation, and neurodegeneration.

Exp Neurol2026PMID:41871753high

Abstract

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

Supports

A tetravalent TREM2 agonistic antibody reduced amyloid pathology in a mouse model of Alzheimer's disease.

Sci Transl Med2022PMID:36070367high

Abstract

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

Supports

Adult-onset CNS myelin sulfatide deficiency is sufficient to cause Alzheimer's disease-like neuroinflammation and cognitive impairment.

Mol Neurodegener2021PMID:34526055medium

Abstract

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

Supports

Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic.

Cell2021PMID:34450028medium

Abstract

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

Supports

CD300f immune receptor contributes to healthy aging by regulating inflammaging, metabolism, and cognitive decline.

Cell Rep2023PMID:37864797medium

Abstract

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

Supports

Brain aging mechanisms with mechanical manifestations.

Mech Ageing Dev2021PMID:34600936medium

Abstract

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

Supports

Effect of peripheral cellular senescence on brain aging and cognitive decline.

Aging Cell2023PMID:36959691high

Abstract

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

Contradicts

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

J Inflamm Res2022PMID:35642214medium

Abstract

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

Contradicts

TREM2, microglia, and Alzheimer's disease.

Mech Ageing Dev2021PMID:33516818medium

Abstract

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

Contradicts

Microglia states and nomenclature: A field at its crossroads.

Neuron2022PMID:36327895medium

Abstract

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

Contradicts

TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy.

Proc Natl Acad Sci U S A2017PMID:29073081medium

Abstract

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

Contradicts

Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology.

Neuron2021PMID:33675684medium

Abstract

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

Contradicts

SYK coordinates neuroprotective microglial responses in neurodegenerative disease.

Cell2022PMID:36257314medium

Abstract

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

Contradicts

Cognitive enhancement and neuroprotective effects of OABL, a sesquiterpene lactone in 5xFAD Alzheimer's disease mice model.

Redox Biol2022PMID:35026701medium

Abstract

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,

Contradicts

Glial reactivity correlates with synaptic dysfunction across aging and Alzheimer's disease.

Nat Commun2025PMID:40593718medium

Abstract

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

Contradicts

Sulfatide deficiency-induced astrogliosis and myelin lipid dyshomeostasis are independent of TREM2-mediated microglial activation.

Nat Commun2026PMID:41513633medium

Abstract

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

Contradicts

cGAS-STING drives ageing-related inflammation and neurodegeneration.

Nature2023PMID:37532932medium

Abstract

Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease

Contradicts

Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes.

Immunity2019PMID:30471926medium

Abstract

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

Contradicts

Lectins and neurodegeneration: A glycobiologist's perspective.

Adv Clin Exp Med2025PMID:40405515medium

Abstract

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

Contradicts

Effect of aging on biomarkers and clinical profile in Parkinson's disease.

J Neurol2025PMID:40991070medium

Abstract

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

Contradicts

Regulation of TREM2 expression by transcription factor YY1 and its protective effect against Alzheimer's disease.

J Biol Chem2023PMID:37044212medium

Abstract

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,

Contradicts

Microglia in Brain Aging and Age-Related Diseases: Friends or Foes?

Int J Mol Sci2025PMID:41373648medium

Abstract

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

Contradicts

Rejuvenating aged microglia by p16(ink4a)-siRNA-loaded nanoparticles increases amyloid-β clearance in animal models of Alzheimer's disease.

Mol Neurodegener2024PMID:38493185medium

Abstract

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

Contradicts

Microglial Replacement Reverses Age-Associated Epigenetic Modifications Despite Accelerating Epigenetic Age.

Aging Dis2025PMID:41135104medium

Abstract

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

Contradicts

Microglial aging in the healthy CNS: phenotypes, drivers, and rejuvenation.

Front Cell Neurosci2013PMID:23493481medium

Abstract

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

📖 Linked Papers

No linked papers recorded for this hypothesis yet.

🏥 Translation

🧬 3D Protein Structure — TREM2

🧬 PDB 6YXY Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

🧠 GTEx v10 Brain ExpressionJSON

Median TPM across 13 brain regions for TREM2, CSF1R from GTEx v10.

💉 Clinical Trials (5)Relevance: 26%

0
Active

0
Completed

1,820
Total Enrolled

NA
Highest Phase

The Signature of Alzheimer's Disease in Subjective Cognitive DeclineUnknown

RECRUITING·NCT07402161 · IRCCS Policlinico S. Donato

250 enrolled · 2025-10-01 · → 2027-10-01

This study focuses on improving early detection of Alzheimer's disease (AD) in patients with subjective cognitive decline (SCD), a preclinical stage of cognitive impairment, in the context of emerging

Subjective Cognitive Decline (SCD) Subjective Cognitive Complaints (SCCs) Subjective Cognitive Impairment

Activity of Cerebral Networks, Amyloid and Microglia in Aging and Alzheimer's DiseaseUnknown

COMPLETED·NCT06224920 · Ludwig-Maximilians - University of Munich

140 enrolled · 2017-01-01 · → 2024-01-01

The temporal sequence of microglial activation, changes in functional and structural connectivity and the progression of neurocognitive deficits has not been conclusively clarified. To date, there hav

Alzheimer Disease Corticobasal Syndrome

magnetic resonance imaging electroencephalography blood and CSF biomarker

Neurofilament Light Chain And Voice Acoustic Analyses In Dementia DiagnosisUnknown

RECRUITING·NCT06339190 · Monash University

1,000 enrolled · 2021-08-01 · → 2025-12

This cohort study aims to determine if a blood test can aid with diagnosing dementia in anyone presenting with cognitive complaints to a single healthcare network. The investigators will measure level

Neurodegenerative Diseases Dementia

Venepuncture

Physical Activity in Patients With Parkinson's Disease: a "Disease Modifying" Intervention?NA

TERMINATED·NCT05815524 · Fondazione Policlinico Universitario Agostino Gemelli IRCCS

30 enrolled · 2022-05-02 · → 2024-12-31

Parkinson's disease (PD) is a neurodegenerative disease characterized by bradykinesia, rigors, and tremor at rest. Distinctive neuropathological signs include progressive loss of dopaminergic neurons

Parkinson Disease

Physical activity training

Clinical, Molecular and Electrophysiological Profiling of Parkinson's Disease: the Role of Non-pharmacological TherapiesNA

UNKNOWN·NCT05807581 · Fondazione Policlinico Universitario Agostino Gemelli IRCCS

400 enrolled · 2023-06-09 · → 2025-05-30

In Parkinson's disease (PD), direct evidence linking inflammation to the harmful activities of alpha-synuclein (a-syn) aggregates, the disease onset, and its progression is still lacking. This transla

Parkinson Disease

physical activity iTBS

No curated ClinVar variants loaded for this hypothesis.

Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.

🔍 Search ClinVar for TREM2, CSF1R →

No DepMap CRISPR Chronos data found for TREM2, CSF1R.

Run python3 scripts/backfill_hypothesis_depmap.py to populate.

💰 Estimated Development

Cost

$0

Timeline

2.0 years

🏆 Tournament

🏆 Arenas / Elo

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📊 Market Indicators

7d Trend

↘

Falling

7d Momentum

▼ 4.6%

Volatility

Low

0.0052

Events (7d)

6

Price History

▼33.2%

💾 Resource Usage

LLM Tokens

18,818

$0.1129

Total Cost

$0.1129

🔮 Predictions

🔎 Predictions vs Observations1 predictions · 0 with recorded observations

Prediction	Predicted	Observed	Status	Conf
If hypothesis is true, intervention targeting TREM2, CSF1R will achieve: TREM2 agonism or modulation reduces microglial dysregulation, decreases neurodegeneration markers, and improves cognitive outco	TREM2 agonism or modulation reduces microglial dysregulation, decreases neurodegeneration markers, and improves cognitive outcomes in animal models or human iPS	— no observation —	pending	0.89

🔮 Falsifiable Predictions (1)

pendingconf 88%

If hypothesis is true, intervention targeting TREM2, CSF1R will achieve: TREM2 agonism or modulation reduces microglial dysregulation, decreases neurodegeneration markers, and improves cognitive outcomes in animal models or human iPSC systems within 12-24 months

Predicted outcome: TREM2 agonism or modulation reduces microglial dysregulation, decreases neurodegeneration markers, and improves cognitive outcomes in animal models or

Falsification: TREM2 agonism fails to reduce neurodegeneration markers or improve cognitive outcomes in validated models

▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate

source	v1_phase_c_backfill
origin_type	gap_debate
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

0%

Debates

0

Incoming

0

Outgoing

0

0 supporting 0 contradicting 0 neutral

View full evidence profile →

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Composite		75%
Mech.		88%
Evidence		78%
Novelty		70%
Feasibility		80%
Impact		76%
Druggability		65%
Safety		58%
Competition		70%
Data avail.		85%
Reproducibility		75%

📗 Cite This Artifact

TREM2-CSF1R Cross-Talk in Microglial Metabolic Reprogramming

🧪 Overview

🧬 Mechanism

⚖️ Evidence

🏥 Translation

🧬 3D Protein Structure — TREM2

💉 Clinical Trials (5)Relevance: 26%

🏆 Tournament

🏆 Arenas / Elo

📊 Market Indicators

💾 Resource Usage

🔮 Predictions

🧬 Related Hypotheses — same target / disease (20)

💬 Discussion

📗 Cite This Artifact

TREM2-CSF1R Cross-Talk in Microglial Metabolic Reprogramming

🧪 Overview

🧬 Mechanism

⚖️ Evidence

🏥 Translation

🧬 3D Protein Structure — TREM2

💉 Clinical Trials (5)Relevance: 26%

🏆 Tournament

🏆 Arenas / Elo

📊 Market Indicators

💾 Resource Usage

🧭 Related

activates (2)

associated with (3)

causes (5)

causes (27-hydroxycholesterol promotes oligodendrocyte mat) (1)

causes (APP overexpression causes selective vulnerability ) (1)

causes (CXCL10 acts as chemokine to recruit cytotoxic CD8+) (1)

causes (CXCL10 antagonists would preserve white matter int) (1)

causes (NAD+ supplementation improves mitophagy and mitoch) (1)

causes (STING activation leads to cellular senescence and ) (1)

causes (age-related activation of cGAS-STING drives microg) (1)

causes (age-related cytokine secretion specifically suppre) (1)

causes (age-related downregulation of AP1S1 disrupts clath) (1)

causes (aging activation of microglia leads to increased C) (1)

causes (aging causes early transcriptomic changes in oligo) (1)

causes (aging mitochondrial dysfunction triggers STING pat) (1)

causes (creates a feed-forward loop of neuroinflammation l) (1)

causes (disrupted cytoskeletal checkpoints lead to prematu) (1)

causes (disrupted endosomal-lysosomal trafficking creates ) (1)

causes (dysregulated microglial transitions fail to suppor) (1)

causes (early proteasome downregulation and dysfunction dr) (1)

causes (enhanced ACE expression in microglia increases Aβ ) (1)

causes (iron-dependent ferroptosis contributes to α-synucl) (1)

causes (loss of sulfatides removes suppression of microgli) (1)

causes (microglia activate CXCL10-mediated recruitment of ) (1)

causes (microglial ACE enhancement activates spleen tyrosi) (1)

causes (microglial activation orchestrates CXCL10-mediated) (1)

causes (proteostasis failure leads to protein aggregation ) (1)

causes (recruited CD8+ T cells promote aging-related white) (1)

causes (recruited CD8+ T cells promote white matter degene) (1)

causes (senescence creates a self-perpetuating cycle by pr) (1)

causes (suppressed mitochondrial function creates vulnerab) (1)

causes (tau aggregation triggers cellular senescence respo) (1)

implicated in (7)

inhibits (1)

investigated in (1)

regulates (1)

targets (1)

🔮 Predictions

🧬 Related Hypotheses — same target / disease (20)

💬 Discussion