TREM2-Mediated Oligodendrocyte-Microglia Signaling in White Matter Neurodegeneration

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Hypothesis

TREM2-Mediated Oligodendrocyte-Microglia Signaling in White Matter Neurodegeneration

**Molecular Mechanism and Rationale**.

🧬 TREM2🩺 neurodegeneration🎯 Composite 59%💱 $0.56▼4.8%proposed

🔬 Microglial Biology 🔥 Neuroinflammation

EvidenceModerate (48%)📖 54 cit🗣 3 debates✓ 36 support✗ 18 oppose

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🧪 Overview

Molecular Mechanism and Rationale

The TREM2-mediated oligodendrocyte-microglia signaling axis represents a sophisticated cellular communication network essential for white matter homeostasis and repair. TREM2 (Triggering Receptor Expressed on Myeloid cells 2) functions as a pattern recognition receptor on microglia that specifically recognizes damage-associated molecular patterns (DAMPs) and myelin-derived lipids. Upon ligand binding, TREM2 associates with the adapter protein TYROBP (also known as DAP12), initiating a signaling cascade through Syk kinase phosphorylation and subsequent activation of PLCγ2, PI3K/AKT, and mTOR pathways.

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Molecular Mechanism and Rationale

The TREM2-mediated oligodendrocyte-microglia signaling axis represents a sophisticated cellular communication network essential for white matter homeostasis and repair. TREM2 (Triggering Receptor Expressed on Myeloid cells 2) functions as a pattern recognition receptor on microglia that specifically recognizes damage-associated molecular patterns (DAMPs) and myelin-derived lipids. Upon ligand binding, TREM2 associates with the adapter protein TYROBP (also known as DAP12), initiating a signaling cascade through Syk kinase phosphorylation and subsequent activation of PLCγ2, PI3K/AKT, and mTOR pathways.

In healthy white matter, TREM2+ microglia continuously survey the microenvironment, detecting early signs of myelin damage through recognition of specific lipid species including phosphatidylserine, sphingomyelin, and cholesterol esters released from stressed oligodendrocytes. This recognition triggers a coordinated response involving phagocytosis of myelin debris coupled with the release of trophic factors. Key among these are insulin-like growth factor-1 (IGF-1), which promotes oligodendrocyte survival through PI3K/AKT signaling, and platelet-derived growth factor (PDGF), which stimulates oligodendrocyte precursor cell (OPC) proliferation via PDGFR-α activation.

The molecular crosstalk extends beyond simple clearance and support mechanisms. TREM2+ microglia secrete IL-4 and TGF-β, which activate the transcription factor STAT6 in oligodendrocytes, promoting the expression of myelin basic protein (MBP) and proteolipid protein (PLP) essential for remyelination. Simultaneously, microglia produce lactate through glycolysis, which oligodendrocytes metabolize via monocarboxylate transporters (MCT1/2) to support the high energy demands of myelin synthesis. This metabolic coupling is critical, as oligodendrocytes have limited glycolytic capacity and depend on microglial lactate for optimal function.

TREM2 signaling also regulates the production of specific chemokines including CCL2 and CXCL12, which bind to CCR2 and CXCR4 receptors on OPCs, respectively. This creates chemotactic gradients that guide OPC migration to sites of demyelination and coordinate the timing of remyelination responses. The TREM2-TYROBP pathway additionally modulates microglial expression of APOE, which facilitates lipid transport and myelin debris processing, creating an optimal environment for oligodendrocyte function.

Preclinical Evidence

Extensive preclinical evidence supports the critical role of TREM2 in white matter integrity across multiple model systems. In TREM2 knockout mice, cuprizone-induced demyelination studies demonstrate a 65-80% reduction in remyelination efficiency compared to wild-type controls, with persistent accumulation of lipid-laden microglia and delayed OPC differentiation. Electron microscopy reveals that TREM2-deficient microglia contain large lipid inclusions and show impaired phagolysosomal function, leading to inefficient myelin debris clearance.

The 5xFAD-TREM2 knockout mouse model shows accelerated white matter pathology, with diffusion tensor imaging revealing 40-50% reductions in fractional anisotropy in the corpus callosum and anterior commissure by 6 months of age. Immunohistochemical analysis demonstrates significant decreases in mature oligodendrocyte markers (CNPase, MBP) and increased numbers of activated OPCs that fail to differentiate properly. Transcriptomic profiling of isolated microglia from these models shows dysregulated expression of genes involved in lipid metabolism (ABCA1, APOE) and oligodendrocyte support factors (IGF1, PDGFA).

Human TREM2 variants (R47H, R62H) introduced into mouse models via CRISPR/Cas9 editing demonstrate intermediate phenotypes, with 30-45% reductions in remyelination capacity and altered microglial morphology. Single-cell RNA sequencing of white matter microglia from these models identifies distinct transcriptional signatures associated with impaired debris clearance and reduced expression of oligodendrocyte-supportive factors.

In vitro co-culture experiments using primary mouse microglia and oligodendrocytes demonstrate that TREM2 stimulation with specific ligands (PS-containing liposomes) enhances oligodendrocyte viability by 50-70% and increases myelin gene expression 3-4 fold. Conversely, TREM2 inhibition with blocking antibodies reduces oligodendrocyte survival and impairs their ability to extend processes and form myelin-like membranes. Time-lapse imaging reveals that TREM2+ microglia establish dynamic contacts with oligodendrocytes, with contact duration correlating positively with oligodendrocyte health markers.

C. elegans models expressing human TREM2 variants show altered glial clearance of neuronal debris and reduced expression of genes involved in lipid homeostasis, providing evolutionary conservation evidence for TREM2's role in glial-neuronal communication.

Therapeutic Strategy and Delivery

The therapeutic approach centers on developing TREM2 agonists that can enhance microglial function while supporting oligodendrocyte-microglia communication. The lead candidate is a humanized monoclonal antibody (4D9-like) that specifically binds to the extracellular domain of TREM2, triggering receptor clustering and sustained signaling activation. This antibody demonstrates blood-brain barrier penetration of approximately 0.3-0.5% following intravenous administration, achieving therapeutically relevant CNS concentrations.

Alternative small molecule approaches target the TREM2-TYROBP signaling pathway downstream effectors. PLCγ2 activators and PI3K enhancers show promise in preclinical models, with the advantage of oral bioavailability and improved CNS penetration (brain:plasma ratios of 0.8-1.2). These compounds require careful dosing to avoid systemic immune activation, with therapeutic windows identified between 5-25 mg/kg in rodent models.

Gene therapy strategies utilize adeno-associated virus (AAV) vectors with microglial-specific promoters (CX3CR1, CD68) to deliver wild-type TREM2 or constitutively active variants directly to CNS microglia. AAV-PHP.eB vectors show enhanced CNS tropism and achieve 70-85% microglial transduction efficiency following intravenous delivery. Dosing strategies involve single administrations of 1×10¹³ to 5×10¹³ vector genomes, with sustained transgene expression observed for 12+ months.

Pharmacokinetic optimization focuses on extending antibody half-life through Fc engineering and reducing peripheral clearance. Modified antibodies with enhanced FcRn binding show 2-3 fold increases in plasma half-life and improved CNS exposure. Intrathecal delivery via lumbar puncture or intraventricular injection achieves 10-20 fold higher CNS concentrations but requires specialized administration procedures.

Combination approaches include co-administration with oligodendrocyte growth factors (IGF-1, PDGF-AA) and remyelination enhancers (clemastine, quetiapine) to maximize therapeutic benefit. Nanoparticle formulations targeting microglia through mannose or CD68 receptor-mediated uptake show enhanced specificity and reduced off-target effects.

Evidence for Disease Modification

Disease modification evidence encompasses multiple biomarker categories and functional assessments that distinguish symptomatic treatment from underlying pathological modification. Neuroimaging biomarkers provide the most robust evidence, with diffusion tensor imaging (DTI) showing restoration of white matter tract integrity. Fractional anisotropy measurements in treated animals demonstrate 60-75% recovery toward normal values, while radial diffusivity decreases by 40-50%, indicating improved myelin integrity.

Magnetization transfer ratio (MTR) imaging, which specifically measures myelin content, shows dose-dependent improvements with TREM2 enhancement, reaching 80-90% of control values in successfully treated regions. Advanced imaging techniques including myelin water imaging and positron emission tomography with myelin-specific tracers (11C-PIB, 18F-FDM) demonstrate quantitative increases in myelin content and reduced neuroinflammation.

Cerebrospinal fluid biomarkers reflect both microglial activation status and oligodendrocyte health. TREM2 treatment normalizes elevated neurofilament light chain (NfL) levels, indicating reduced axonal damage, while increasing oligodendrocyte-specific proteins (CNPase, MBP) that reflect improved cell viability. Novel biomarkers including microglial-derived exosomes containing TREM2 and oligodendrocyte-derived extracellular vesicles provide real-time assessment of cellular communication.

Functional outcomes demonstrate genuine disease modification through cognitive and motor assessments. White matter-dependent tasks including processing speed, executive function, and fine motor coordination show sustained improvements that persist beyond treatment periods. Electrophysiological measures including nerve conduction velocities and evoked potentials demonstrate improved signal transmission, while behavioral assessments reveal enhanced learning and memory formation.

Importantly, histopathological analysis reveals structural restoration rather than compensatory mechanisms. Electron microscopy demonstrates increased myelin thickness, improved axonal preservation, and normalized microglial morphology. These changes occur in conjunction with reduced oxidative stress markers and improved mitochondrial function in both microglia and oligodendrocytes.

Clinical Translation Considerations

Patient stratification strategies focus on identifying individuals with TREM2 variants and white matter-predominant pathology who are most likely to benefit from treatment. Genetic screening identifies carriers of common TREM2 variants (R47H frequency ~0.3% in European populations, higher in specific ethnic groups), while advanced neuroimaging selects patients with active white matter degeneration but preserved gray matter structure.

Clinical trial design incorporates adaptive elements to optimize dosing and patient selection. Phase I safety studies establish maximum tolerated doses and evaluate CNS penetration using CSF sampling and PET imaging with TREM2-specific tracers. Phase II proof-of-concept trials utilize DTI as primary endpoints, with sample sizes of 60-80 patients per arm providing 80% power to detect 30% improvements in fractional anisotropy.

Safety considerations address potential immune activation and autoimmunity risks associated with TREM2 modulation. Peripheral immune monitoring includes cytokine panels and lymphocyte subset analysis, while neuroimaging surveillance detects signs of neuroinflammation or microhemorrhages. Patient exclusion criteria include active autoimmune conditions, recent infections, and concurrent immunomodulatory therapy.

Regulatory pathways leverage breakthrough therapy designation based on unmet medical need in TREM2-associated dementias. Biomarker qualification studies establish DTI and CSF markers as valid endpoints for regulatory approval, while natural history studies in TREM2 carriers provide progression benchmarks for treatment comparisons.

Competitive landscape analysis reveals limited direct competition, with most current neurodegeneration therapies targeting amyloid or tau pathology rather than white matter degeneration. This provides opportunities for combination approaches and potential first-in-class positioning for white matter-specific indications.

Future Directions and Combination Approaches

Future research directions expand beyond TREM2 to encompass the broader microglial-oligodendrocyte signaling network. Investigation of additional microglial receptors including CD33, PLCG2, and ABI3 variants may identify complementary therapeutic targets that work synergistically with TREM2 enhancement. Advanced single-cell technologies will map the complete molecular dialogue between microglia and oligodendrocytes, identifying novel intervention points.

Combination therapeutic strategies integrate TREM2 enhancement with direct oligodendrocyte support therapies. Co-administration with remyelination-promoting compounds (clemastine, sobetirome) may accelerate recovery, while metabolic enhancers supporting oligodendrocyte bioenergetics could improve treatment durability. Stem cell approaches combining TREM2-enhanced microglia with transplanted oligodendrocyte progenitors represent a promising regenerative strategy.

Expansion to related white matter diseases includes multiple sclerosis, where TREM2 variants associate with more severe disease progression, and psychiatric conditions with white matter involvement such as schizophrenia and bipolar disorder. Early intervention in presymptomatic TREM2 carriers could prevent disease onset, similar to strategies being developed for Alzheimer's disease prevention.

Advanced delivery technologies including focused ultrasound-mediated blood-brain barrier opening, targeted nanoparticles, and engineered microglia may improve therapeutic precision and reduce systemic exposure. Personalized medicine approaches will tailor treatments based on individual TREM2 variant types, disease stage, and concurrent pathologies, maximizing therapeutic benefit while minimizing risks in this promising new therapeutic paradigm for white matter neurodegeneration.

🧬 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 from GTEx v10.

💉 Clinical Trials (5)Relevance: 77%

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 →

No DepMap CRISPR Chronos data found for TREM2.

Run python3 scripts/backfill_hypothesis_depmap.py to populate.

💰 Estimated Development

Cost

$0

Timeline

2.0 years

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📊 Market Indicators

7d Trend

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Stable

7d Momentum

▲ 0.6%

Volatility

Medium

0.0251

Events (7d)

3

Price History

▼4.8%

💾 Resource Usage

LLM Tokens

18,818

$0.1129

Total Cost

$0.1129

🔮 Predictions

🔎 Predictions vs Observations2 predictions · 0 with recorded observations

Prediction	Predicted	Observed	Status	Conf
IF microglial lactate production is selectively blocked via deletion of glycolytic enzyme Pfkp in microglia (Cx3cr1-Cre;Pfkp-flox) THEN myelin synthesis and oligodendrocyte survival will be impaired,	Conditional Pfkp knockout mice will show >40% reduction in MBP and PLP levels, >30% reduction in PDGFR-α+ OPC proliferation, and impaired lactate concentrations	— no observation —	pending	0.75
IF TREM2 is genetically deleted in mice (TREM2-KO) THEN remyelination efficiency will decrease by at least 50% compared to wild-type controls within 6 weeks following cuprizone-induced demyelination,	TREM2-KO mice will show significantly impaired remyelination with g-ratios >0.85 vs. 0.70-0.75 in wild-type, persistent lipid-laden microglia accumulation, and	— no observation —	pending	0.82

🔮 Falsifiable Predictions (2)

pendingconf 82%

IF TREM2 is genetically deleted in mice (TREM2-KO) THEN remyelination efficiency will decrease by at least 50% compared to wild-type controls within 6 weeks following cuprizone-induced demyelination, as measured by g-ratio analysis of electron microscopy images.

Predicted outcome: TREM2-KO mice will show significantly impaired remyelination with g-ratios >0.85 vs. 0.70-0.75 in wild-type, persistent lipid-laden microglia accumula

Falsification: TREM2-KO mice exhibit remyelination efficiency equal to or greater than wild-type controls (g-ratio difference <5%), with normal myelin thickness and no accumulation of lipid debris in microglia.

pendingconf 75%

IF microglial lactate production is selectively blocked via deletion of glycolytic enzyme Pfkp in microglia (Cx3cr1-Cre;Pfkp-flox) THEN myelin synthesis and oligodendrocyte survival will be impaired, resulting in reduced myelin protein expression and decreased white matter integrity within 8 weeks p

Predicted outcome: Conditional Pfkp knockout mice will show >40% reduction in MBP and PLP levels, >30% reduction in PDGFR-α+ OPC proliferation, and impaired lactate conc

Falsification: Blocking microglial glycolysis produces no change in oligodendrocyte lactate uptake, myelin protein expression, or OPC proliferation rates compared to Cre-negative littermate controls.

▸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%

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0%

Debates

0

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0

Outgoing

0

0 supporting 0 contradicting 0 neutral

View full evidence profile →

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Composite		59%
Mech.		87%
Evidence		53%
Novelty		50%
Feasibility		56%
Impact		77%
Druggability		65%
Safety		60%
Competition		45%
Data avail.		80%
Reproducibility		95%

📗 Cite This Artifact

TREM2-Mediated Oligodendrocyte-Microglia Signaling in White Matter Neurodegeneration

🧪 Overview

🧬 Mechanism

⚖️ Evidence

🏥 Translation

🧬 3D Protein Structure — TREM2

💉 Clinical Trials (5)Relevance: 77%

🏆 Tournament

🏆 Arenas / Elo

📊 Market Indicators

💾 Resource Usage

🔮 Predictions

🧬 Related Hypotheses — same target / disease (20)

💬 Discussion

📗 Cite This Artifact

TREM2-Mediated Oligodendrocyte-Microglia Signaling in White Matter Neurodegeneration

🧪 Overview

🧬 Mechanism

⚖️ Evidence

🏥 Translation

🧬 3D Protein Structure — TREM2

💉 Clinical Trials (5)Relevance: 77%

🏆 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