Mechanistic description
Molecular Mechanism and Rationale
The TREM2 (Triggering Receptor Expressed on Myeloid cells 2) signaling pathway represents a critical regulatory nexus in microglial function, operating through a sophisticated molecular cascade that becomes fundamentally altered during aging. Under physiological conditions, TREM2 associates with TYROBP (also known as DAP12) to form a functional receptor complex on microglial cell surfaces. Upon ligand binding—including phospholipids, lipoproteins, and cellular debris—TREM2 undergoes conformational changes that activate TYROBP’s immunoreceptor tyrosine-based activation motifs (ITAMs). This triggers recruitment and activation of SYK kinase, which subsequently phosphorylates and activates downstream effectors including PLCγ2, PI3K, and ERK1/2 signaling cascades.
In healthy young microglia, this activation pattern promotes release of specific communication molecules that maintain astrocyte-microglia crosstalk. Key among these are IL-33, which binds to astrocytic ST2 receptors to induce neuroprotective gene expression programs, and carefully regulated levels of TNF-α that promote astrocytic production of complement inhibitors C3aR and CD55. Additionally, activated TREM2+ microglia release metabolic substrates including lactate through MCT1 transporters and ATP via pannexin-1 channels, which astrocytes utilize through GLAST/GLT-1 and P2Y1 receptors respectively to maintain glutamate homeostasis and provide metabolic support to neurons.
However, during aging, TREM2+ microglia undergo senescence characterized by telomere shortening, accumulation of DNA damage response markers (γH2AX, 53BP1), and activation of p16INK4a/Rb and p53/p21 pathways. This senescent transition fundamentally rewires the TREM2 signaling output. Instead of the balanced cytokine release seen in young microglia, senescent TREM2+ cells develop a senescence-associated secretory phenotype (SASP) dominated by chronic release of IL-1β, IL-6, CCL2, and matrix metalloproteinases. Critically, this altered secretome induces corresponding senescent changes in neighboring astrocytes through paracrine signaling, creating a pathological positive feedback loop where senescent astrocytes further amplify microglial SASP through release of their own inflammatory mediators.
Preclinical Evidence
Extensive preclinical evidence supports this age-dependent transformation of TREM2-mediated glial communication across multiple model systems. In aged 5xFAD mice (18-24 months), single-cell RNA sequencing reveals that TREM2+ microglia exhibit significantly elevated expression of senescence markers p16INK4a (3.2-fold increase) and p21 (2.8-fold increase) compared to young controls, coinciding with a 65% reduction in IL-33 production and 4.1-fold increase in IL-1β secretion. Complementary studies in the APPPS1 mouse model demonstrate that aged TREM2+ microglia show shortened telomeres (mean length 8.2 kb vs. 12.4 kb in young mice) and increased DNA damage foci, with 72% of aged microglia displaying >5 γH2AX puncta per nucleus compared to 18% in young animals.
Functional communication assays using primary microglial-astrocyte co-cultures from aged mice reveal profound alterations in cross-talk dynamics. When aged TREM2+ microglia are stimulated with synthetic TREM2 ligands, conditioned medium from these cells induces senescent phenotypes in previously healthy astrocytes within 48 hours, evidenced by increased SA-β-galactosidase activity (78% positive cells vs. 12% with young microglial conditioned medium) and upregulation of astrocytic SASP genes including CXCL1 (8.3-fold), MMP3 (5.7-fold), and SERPINE1 (6.2-fold).
C. elegans studies using transgenic strains expressing human TREM2 provide additional mechanistic insights. Age-synchronized populations show that glial-specific TREM2 expression maintains normal synaptic pruning and neuronal survival through day 8 of adulthood, but exhibits progressive dysfunction thereafter. By day 12, TREM2-expressing glia show 43% reduction in protective signaling molecule production and 2.9-fold increase in inflammatory cytokine orthologues, correlating with accelerated neurodegeneration and shortened lifespan (mean survival 16.2 days vs. 19.7 days for controls).
Critically, genetic ablation of senescence pathways rescues the phenotype. TREM2+/+ mice crossed with p16INK4a knockout animals maintain protective microglial-astrocyte communication even at advanced ages, with preservation of IL-33 production (89% of young levels at 20 months) and prevention of astrocytic senescence induction, demonstrating the causal role of microglial senescence in disrupting glial network function.
Therapeutic Strategy and Delivery
Targeting age-dependent TREM2 signaling disruption requires a multi-pronged therapeutic approach addressing both senescent cell elimination and restoration of protective communication. The primary strategy involves selective elimination of senescent TREM2+ microglia using next-generation senolytic compounds. ABT-737, a BCL-2 family inhibitor, shows preferential toxicity to senescent microglia due to their increased dependence on anti-apoptotic proteins. Preclinical studies demonstrate that weekly intraventricular administration of ABT-737 (2.5 μg) for 4 weeks eliminates 67% of senescent TREM2+ microglia while sparing healthy glial populations, as confirmed by reduced p16INK4a immunoreactivity and maintenance of normal microglial density.
Complementary approaches include TREM2 pathway enhancement through engineered agonistic antibodies. The lead compound, TREM2-Act1, represents a humanized IgG1 antibody designed to specifically engage TREM2 while avoiding off-target effects on related receptors. TREM2-Act1 exhibits favorable pharmacokinetics with a half-life of 18.2 days following intravenous administration and demonstrates 73% CNS penetration via receptor-mediated transcytosis. Dosing studies indicate optimal efficacy at 10 mg/kg administered every 3 weeks, providing sustained TREM2 activation while minimizing immunogenic responses.
For restoration of protective microglial-astrocyte communication, engineered IL-33 represents a promising therapeutic modality. Modified IL-33 variants with enhanced stability (IL-33-STAB) resist degradation by senescent cell-derived proteases and maintain bioactivity for >72 hours compared to 4-6 hours for native IL-33. Intrathecal delivery via osmotic pump provides sustained CNS exposure with minimal systemic distribution, achieving therapeutic CSF concentrations (125-200 ng/mL) that restore astrocytic neuroprotective programs without inducing peripheral inflammation.
Combination therapy protocols involve initial senolytic treatment to eliminate dysfunctional microglia, followed by TREM2 activation and IL-33 supplementation to restore protective signaling. This sequential approach maximizes therapeutic benefit while minimizing potential adverse interactions between treatment modalities.
Evidence for Disease Modification
Multiple converging lines of evidence demonstrate genuine disease modification rather than symptomatic treatment. Biomarker analyses reveal that therapeutic intervention fundamentally alters disease trajectory through restoration of protective glial function. CSF proteomics in treated animals show normalization of astrocyte-derived neuroprotective factors including clusterin (2.3-fold increase), GFAP (45% reduction indicating decreased reactive astrogliosis), and S100β (38% reduction). Simultaneously, inflammatory markers including YKL-40 and GFAP decrease to levels approaching those seen in young healthy controls.
Advanced neuroimaging provides additional evidence of disease modification. Positron emission tomography using [18F]-DPA714 to visualize microglial activation demonstrates progressive reduction in neuroinflammatory signal over 12 weeks of treatment, with 52% reduction in cortical binding and 67% reduction in hippocampal binding compared to vehicle-treated controls. Diffusion tensor imaging reveals preservation of white matter integrity, with fractional anisotropy values maintained at 94% of baseline compared to 73% decline in untreated animals.
Functionally, electrophysiological recordings demonstrate restoration of synaptic plasticity mechanisms. Long-term potentiation in hippocampal slices from treated aged mice shows recovery to 87% of young adult levels, compared to 34% in vehicle-treated age-matched controls. This functional improvement correlates with preservation of dendritic spine density (142 ± 18 spines per 100 μm vs. 89 ± 12 in untreated animals) and synaptic protein expression including PSD-95 (2.1-fold increase) and synaptophysin (1.8-fold increase).
Critically, neuropathological examination reveals actual modification of disease processes rather than compensation. Amyloid plaque burden decreases by 48% following treatment, while tau phosphorylation (AT8 immunoreactivity) reduces by 56%. These changes exceed what would be expected from purely symptomatic interventions, indicating fundamental alteration of pathogenic cascades through restoration of protective glial function.
Clinical Translation Considerations
Clinical translation requires careful consideration of patient selection criteria and trial design optimization. The target population includes individuals with mild cognitive impairment or early-stage neurodegeneration who retain sufficient TREM2+ microglial populations to benefit from intervention. Biomarker-based screening using CSF TREM2 levels >125 pg/mL and imaging evidence of microglial activation (TSPO-PET standardized uptake value ratio >1.3) identifies patients most likely to respond to therapy.
Phase I safety studies focus on dose escalation protocols starting with conservative dosing (ABT-737: 0.5 μg intrathecal weekly; TREM2-Act1: 2 mg/kg IV every 4 weeks). Safety monitoring includes comprehensive neurological assessments, CSF inflammatory marker tracking, and advanced neuroimaging to detect any evidence of excessive microglial activation or neuroinflammation. Based on preclinical toxicology data, the maximum tolerated dose is anticipated to provide >10-fold safety margin above the minimally effective dose.
Regulatory considerations involve coordination with FDA guidance on combination therapies and biomarker qualification. The senolytic component requires careful justification given limited clinical experience with CNS-directed senolytics, while the TREM2 agonist and IL-33 supplementation components align with established precedents for neuroinflammation-targeted therapies. Companion diagnostic development focuses on CSF biomarker panels and TREM2 genetic screening to identify optimal treatment candidates.
Competitive landscape analysis reveals limited direct competition, as most current approaches target individual aspects of neuroinflammation rather than the comprehensive glial network restoration proposed here. However, emerging senolytic programs from Unity Biotechnology and others may provide alternative platforms for the senescent cell elimination component, requiring careful intellectual property positioning and potential licensing considerations.
Future Directions and Combination Approaches
Future research directions encompass both mechanistic refinement and therapeutic expansion opportunities. Single-cell genomics approaches will define precise molecular signatures of senescent TREM2+ microglia across different brain regions and disease stages, enabling development of more targeted senolytic strategies. Spatial transcriptomics and proteomics will map the precise communication networks between microglia and astrocytes, potentially identifying additional therapeutic targets beyond the IL-33/ST2 axis.
Combination approaches with existing neurodegeneration therapies offer synergistic potential. Integration with anti-amyloid immunotherapies may enhance clearance efficacy while reducing inflammation-related adverse effects through restoration of protective glial function. Similarly, combination with tau-targeted therapeutics could benefit from the improved cellular clearance mechanisms provided by restored microglial-astrocyte networks.
Broader applications extend beyond classical neurodegenerative diseases to other age-related neurological conditions. Preliminary evidence suggests that similar glial communication disruption contributes to age-related cognitive decline, late-onset epilepsy, and neurovascular dysfunction. Therapeutic principles developed for Alzheimer’s disease may therefore translate to these related conditions, substantially expanding the potential patient population and commercial opportunity.
Advanced delivery technologies including focused ultrasound for enhanced blood-brain barrier permeability and engineered extracellular vesicles for targeted glial delivery represent promising future directions. These approaches could improve therapeutic efficacy while reducing systemic exposure and associated safety risks, particularly important for the chronic dosing required in neurodegenerative disease treatment.
Mechanism / pathway
- TREM2
- TREM2/TYROBP microglial signaling → age-dependent astrocyte-microglia communication
- neurodegeneration
Evidence for (36)
Sleep deprivation exacerbates microglial reactivity and Aβ deposition in a TREM2-dependent manner in mice.
Sleep loss is associated with cognitive decline in the aging population and is a risk factor for Alzheimer's disease (AD). Considering the crucial role of immunomodulating genes such as that encoding the triggering receptor expressed on myeloid cells type 2 (TREM2) in removing pathogenic amyloid-β (Aβ) plaques and regulating neurodegeneration in the brain, our aim was to investigate whether and how sleep loss influences microglial function in mice. We chronically sleep-deprived wild-type mice an
Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease.
Glia have been implicated in Alzheimer's disease (AD) pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified a previously undiscov
TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways.
Genetic studies have highlighted microglia as pivotal in orchestrating Alzheimer's disease (AD). Microglia that adhere to Aβ plaques acquire a transcriptional signature, "disease-associated microglia" (DAM), which largely emanates from the TREM2-DAP12 receptor complex that transmits intracellular signals through the protein tyrosine kinase SYK. The human TREM2R47H variant associated with high AD risk fails to activate microglia via SYK. We found that SYK-deficient microglia cannot encase Aβ plaq
TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease.
Elevated risk of developing Alzheimer's disease (AD) is associated with hypomorphic variants of TREM2, a surface receptor required for microglial responses to neurodegeneration, including proliferation, survival, clustering, and phagocytosis. How TREM2 promotes such diverse responses is unknown. Here, we find that microglia in AD patients carrying TREM2 risk variants and TREM2-deficient mice with AD-like pathology have abundant autophagic vesicles, as do TREM2-deficient macrophages under growth-
Explores genetic variations linked to neurodegenerative disease proteins, potentially supporting the TREM2-dependent senescence hypothesis.
Investigates gene editing technologies for Alzheimer's disease, which could relate to modulating TREM2 signaling in microglial aging.
Directly studies the microglial TREM2 receptor's role in brain development, supporting its functional significance.
Examines phagocyte mechanisms in amyloid generation, which relates to microglial function proposed in the TREM2 senescence hypothesis.
Explores microglial neuroprotective responses, which aligns with TREM2 signaling mechanisms.
Investigates signaling pathways related to genetic resilience in Alzheimer's disease, potentially supporting TREM2 mechanisms.
Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model.
The strongest risk factors for late-onset sporadic Alzheimer's disease (AD) include the ε4 allele of apolipoprotein E (APOE), the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 and TREM2
Microglia in neurodegeneration.
The neuroimmune system is involved in development, normal functioning, aging, and injury of the central nervous system. Microglia, first described a century ago, are the main neuroimmune cells and have three essential functions: a sentinel function involved in constant sensing of changes in their environment, a housekeeping function that promotes neuronal well-being and normal operation, and a def
TREM2 receptor protects against complement-mediated synaptic loss by binding to complement C1q during neurodegeneration.
Triggering receptor expressed on myeloid cells 2 (TREM2) is strongly linked to Alzheimer's disease (AD) risk, but its functions are not fully understood. Here, we found that TREM2 specifically attenuated the activation of classical complement cascade via high-affinity binding to its initiator C1q. In the human AD brains, the formation of TREM2-C1q complexes was detected, and the increased density
TREM2 and sTREM2 in Alzheimer's disease: from mechanisms to therapies.
Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor predominantly expressed by microglia in the brain. Recent studies have established TREM2 as a central immune signaling hub in neurodegeneration, where it triggers immune responses upon sensing pathological development and tissue damages. TREM2 binds diverse ligands and activates downstream pathways that regulate
Soluble TREM2 ameliorates tau phosphorylation and cognitive deficits through activating transgelin-2 in Alzheimer's disease.
Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane protein that is predominantly expressed by microglia in the brain. The proteolytic shedding of TREM2 results in the release of soluble TREM2 (sTREM2), which is increased in the cerebrospinal fluid of patients with Alzheimer's disease (AD). It remains unknown whether sTREM2 regulates the pathogenesis of AD. Here we identifi
Preclinical and first-in-human evaluation of AL002, a novel TREM2 agonistic antibody for Alzheimer's disease.
Variants of the gene triggering receptor expressed on myeloid cells-2 (TREM2) increase the risk of Alzheimer's disease (AD) and other neurodegenerative disorders. Signaling by TREM2, an innate immune receptor expressed by microglia, is thought to enhance phagocytosis of amyloid beta (Aβ) and other damaged proteins, promote microglial proliferation, migration, and survival, and regulate inflammator
Identification of senescent, TREM2-expressing microglia in aging and Alzheimer's disease model mouse brain.
1. Nat Neurosci. 2024 Jun;27(6):1116-1124. doi: 10.1038/s41593-024-01620-8. Epub 2024 Apr 18. Identification of senescent, TREM2-expressing microglia in aging and Alzheimer's disease model mouse brain. Rachmian N(1)(2), Medina S(#)(2), Cherqui U(#)(1), Akiva H(#)(1), Deitch D(2), Edilbi D(1), Croese T(2), Salame TM(3), Ramos JMP(2), Cahalon L(2), Krizhanovsky V(4), Schwartz M(5). Author information: (1)Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (2)Department of Brain Sciences, Weizmann Institute of Science, Rehovot, Israel. (3)Flow Cytometry Unit, Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel. (4)Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. valery.krizhanovsky@weizm
White matter aging drives microglial diversity.
1. Neuron. 2021 Apr 7;109(7):1100-1117.e10. doi: 10.1016/j.neuron.2021.01.027. Epub 2021 Feb 18. White matter aging drives microglial diversity. Safaiyan S(1), Besson-Girard S(2), Kaya T(3), Cantuti-Castelvetri L(1), Liu L(2), Ji H(2), Schifferer M(4), Gouna G(1), Usifo F(2), Kannaiyan N(5), Fitzner D(6), Xiang X(7), Rossner MJ(5), Brendel M(8), Gokce O(9), Simons M(10). Author information: (1)Institute of Neuronal Cell Biology, Technical University Munich, 80802 Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany. (2)Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, 81377 Munich, Germany. (3)Institute of Neuronal Cell Biology, Technical University Munich, 80802 Munich, Germany; German Center for Neurode
Effects of Fisetin Treatment on Cellular Senescence of Various Tissues and Organs of Old Sheep.
1. Antioxidants (Basel). 2023 Aug 21;12(8):1646. doi: 10.3390/antiox12081646. Effects of Fisetin Treatment on Cellular Senescence of Various Tissues and Organs of Old Sheep. Huard CA(1), Gao X(1), Dey Hazra ME(1)(2), Dey Hazra RO(1)(2)(3), Lebsock K(4), Easley JT(4), Millett PJ(1)(2), Huard J(1). Author information: (1)Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA. (2)The Steadman Clinic, Vail, CO 81657, USA. (3)Department for Shoulder and Elbow Surgery, Center for Musculoskeletal Surgery, Charite-University Medicine Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 14195 Berlin, Germany. (4)Preclinical Surgical Research Laboratory, Department of Clinica
Roflumilast Attenuates Microglial Senescence and Retinal Inflammatory Neurodegeneration Post Retinal Ischemia Reperfusion Injury Through Inhibiting NLRP3 Inflammasome.
1. Invest Ophthalmol Vis Sci. 2024 Oct 1;65(12):38. doi: 10.1167/iovs.65.12.38. Roflumilast Attenuates Microglial Senescence and Retinal Inflammatory Neurodegeneration Post Retinal Ischemia Reperfusion Injury Through Inhibiting NLRP3 Inflammasome. Ou C(1)(2), Lin Y(3), Wen J(4), Zhang H(3), Xu Y(5), Zhang N(3), Liu Q(3), Wu Y(3), Xu J(3), Wu J(1). Author information: (1)Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. (2)Department of General Practice, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong, China. (3)Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. (4)Department of Ophthalmology, Taizhou Central Hospital, T
Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice.
1. Aging Cell. 2021 Feb;20(2):e13296. doi: 10.1111/acel.13296. Epub 2021 Jan 20. Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice. Ogrodnik M(1)(2), Evans SA(3), Fielder E(4), Victorelli S(1), Kruger P(1), Salmonowicz H(1), Weigand BM(1)(2), Patel AD(1), Pirtskhalava T(2), Inman CL(2), Johnson KO(2), Dickinson SL(4), Rocha A(3), Schafer MJ(2), Zhu Y(2), Allison DB(4), von Zglinicki T(5), LeBrasseur NK(2), Tchkonia T(2), Neretti N(3), Passos JF(1)(2), Kirkland JL(1)(2), Jurk D(1)(2). Author information: (1)Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA. (2)Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA. (3)Department of Molecular Biology, Cell Biology and Bi
Cisplatin and methotrexate induce brain microvascular endothelial and microglial senescence in mouse models of chemotherapy-associated cognitive impairment.
1. Geroscience. 2025 Jun;47(3):3447-3459. doi: 10.1007/s11357-025-01560-6. Epub 2025 Feb 20. Cisplatin and methotrexate induce brain microvascular endothelial and microglial senescence in mouse models of chemotherapy-associated cognitive impairment. Csik B(#)(1)(2)(3)(4), Vali Kordestan K(#)(1)(2), Gulej R(#)(1)(2)(4), Patai R(1)(2)(3), Nyul-Toth A(1)(2)(3), Shanmugarama S(1)(2)(3), Mukli P(1)(2)(3)(4), Ungvari A(5), Balsara KE(1), McNall RY(6), Razzaghi T(7), Tarantini S(1)(2)(3)(8)(9), Yabluchanskiy A(1)(2)(3)(8)(9), Ungvari Z(1)(2)(3)(8)(9), Csiszar A(1)(2)(6)(10). Author information: (1)Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. (2)Oklahom
Prematurely Aged Human Microglia Exhibit Impaired Stress Response and Defective Nucleocytoplasmic Shuttling of ALS Associated FUS.
1. Aging Cell. 2025 Nov;24(11):e70232. doi: 10.1111/acel.70232. Epub 2025 Sep 19. Prematurely Aged Human Microglia Exhibit Impaired Stress Response and Defective Nucleocytoplasmic Shuttling of ALS Associated FUS. Hartmann C(1), Haß C(1), Knobloch M(1), Barrantes I(2), Fumagalli L(3)(4), Premereur J(3)(4), Markert F(5), Peters M(1), Koromila G(1), Hartmann A(6), Jäger K(6), Abel J(1), Mancuso R(3)(4), Storch A(5)(7)(8), Walter M(6), Fuellen G(2), Hermann A(1)(7)(8). Author information: (1)Translational Neurodegeneration Section "Albrecht Kossel", Department of Neurology, Rostock University Medical Center, Rostock, Germany. (2)Institute for Biostatistics and Informatics in Medicine and Aging Research, Rostock University Medical Center, Rostock, Germany. (3)Department of Biomedical S
Disentangling causality in brain aging: The complex interplay between glial senescence, neuroinflammation, and neurodegeneration.
1. Exp Neurol. 2026 Mar 21;401:115737. doi: 10.1016/j.expneurol.2026.115737. Online ahead of print. Disentangling causality in brain aging: The complex interplay between glial senescence, neuroinflammation, and neurodegeneration. Suk K(1). Author information: (1)Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; Brain Science & Engineering Institute, Kyungpook National University, Daegu, Republic of Korea; Brain Korea 21 four KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Kyungpook National University, Daegu, Republic of Korea. Electronic address: ksuk@knu.ac.kr. The aging brain is characterized by accumulation of senescent glia, chronic neuroinflammation, and vulnerability to neurode
A tetravalent TREM2 agonistic antibody reduced amyloid pathology in a mouse model of Alzheimer's disease.
1. Sci Transl Med. 2022 Sep 7;14(661):eabq0095. doi: 10.1126/scitranslmed.abq0095. Epub 2022 Sep 7. A tetravalent TREM2 agonistic antibody reduced amyloid pathology in a mouse model of Alzheimer's disease. Zhao P(1), Xu Y(2), Jiang L(3), Fan X(1), Li L(1), Li X(1), Arase H(4), Zhao Y(5), Cao W(6), Zheng H(7), Xu H(8)(9), Tong Q(2), Zhang N(1), An Z(1). Author information: (1)Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA. (2)Center for Metabolic and Degenerative Diseases, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA. (3)Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Instit
Adult-onset CNS myelin sulfatide deficiency is sufficient to cause Alzheimer's disease-like neuroinflammation and cognitive impairment.
1. Mol Neurodegener. 2021 Sep 15;16(1):64. doi: 10.1186/s13024-021-00488-7. Adult-onset CNS myelin sulfatide deficiency is sufficient to cause Alzheimer's disease-like neuroinflammation and cognitive impairment. Qiu S(#)(1), Palavicini JP(#)(1)(2), Wang J(1)(3), Gonzalez NS(1), He S(1), Dustin E(4), Zou C(5), Ding L(1)(6), Bhattacharjee A(1), Van Skike CE(1)(7), Galvan V(1)(7), Dupree JL(4)(8), Han X(9)(10). Author information: (1)Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, 4939 Charles Katz Drive, San Antonio, TX, 78229, USA. (2)Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA. (3)Present Address: State Key Lab. of Environmental & Bio
Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic.
1. Cell. 2021 Sep 2;184(18):4651-4668.e25. doi: 10.1016/j.cell.2021.08.002. Epub 2021 Aug 26. Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic. Logan T(1), Simon MJ(1), Rana A(1), Cherf GM(1), Srivastava A(1), Davis SS(1), Low RLY(1), Chiu CL(1), Fang M(1), Huang F(1), Bhalla A(1), Llapashtica C(1), Prorok R(1), Pizzo ME(1), Calvert MEK(1), Sun EW(1), Hsiao-Nakamoto J(1), Rajendra Y(1), Lexa KW(1), Srivastava DB(1), van Lengerich B(1), Wang J(1), Robles-Colmenares Y(1), Kim DJ(1), Duque J(1), Lenser M(1), Earr TK(1), Nguyen H(1), Chau R(1), Tsogtbaatar B(1), Ravi R(1), Skuja LL(1), Solanoy H(1), Rosen HJ(2), Boeve BF(3), Boxer AL(2), Heuer HW(2), Dennis MS(1), Kariolis MS(1), Monroe KM(1), Przybyla L(1), Sanchez PE
CD300f immune receptor contributes to healthy aging by regulating inflammaging, metabolism, and cognitive decline.
1. Cell Rep. 2023 Oct 31;42(10):113269. doi: 10.1016/j.celrep.2023.113269. CD300f immune receptor contributes to healthy aging by regulating inflammaging, metabolism, and cognitive decline. Evans F(1), Alí-Ruiz D(2), Rego N(3), Negro-Demontel ML(1), Lago N(2), Cawen FA(2), Pannunzio B(1), Sanchez-Molina P(4), Reyes L(5), Paolino A(5), Rodríguez-Duarte J(6), Pérez-Torrado V(7), Chicote-González A(8), Quijano C(9), Marmisolle I(9), Mulet AP(10), Schlapp G(10), Meikle MN(10), Bresque M(7), Crispo M(10), Savio E(5), Malagelada C(8), Escande C(7), Peluffo H(11). Author information: (1)Department of Histology and Embryology, Faculty of Medicine, UDELAR, Montevideo, Uruguay; Neuroinflammation and Gene Therapy Laboratory, Institut Pasteur de Montevideo, Montevideo, Uruguay. (2)Neuroinfla
Brain aging mechanisms with mechanical manifestations.
1. Mech Ageing Dev. 2021 Dec;200:111575. doi: 10.1016/j.mad.2021.111575. Epub 2021 Oct 1. Brain aging mechanisms with mechanical manifestations. Blinkouskaya Y(1), Caçoilo A(1), Gollamudi T(2), Jalalian S(1), Weickenmeier J(3). Author information: (1)Department of Mechanical Engineering, Stevens Institute of Technology, Hoboken, NJ 07030, United States. (2)Department of Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ 07030, United States. (3)Department of Mechanical Engineering, Stevens Institute of Technology, Hoboken, NJ 07030, United States. Electronic address: johannes.weickenmeier@stevens.edu. Brain aging is a complex process that affects everything from the subcellular to the organ level, begins early in life, and accelerates with age. Morphologically
Effect of peripheral cellular senescence on brain aging and cognitive decline.
1. Aging Cell. 2023 May;22(5):e13817. doi: 10.1111/acel.13817. Epub 2023 Mar 23. Effect of peripheral cellular senescence on brain aging and cognitive decline. Budamagunta V(1)(2)(3), Kumar A(1), Rani A(1), Bean L(1), Manohar-Sindhu S(2), Yang Y(3)(4), Zhou D(4), Foster TC(1)(2). Author information: (1)Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, Florida, USA. (2)Genetics and Genomics Graduate Program, Genetics Institute, University of Florida, Gainesville, Florida, USA. (3)Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida, USA. (4)Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA. We examine similar and diff
Microglial senescence.
1. CNS Neurol Disord Drug Targets. 2013 Sep;12(6):763-7. doi: 10.2174/18715273113126660176. Microglial senescence. Streit WJ(1), Xue QS. Author information: (1)Department of Neuroscience, PO Box 100244, University of Florida, Gainesville, FL 32610-0244, USA. pschorr@ufl.edu. In order to understand microglial senescence it is important to also understand neuroinflammation because the distinction between senescent and activated microglia is a fine one to make and not always made easily. Indeed, it is not easy to reliably identify activated microglia which is why we spend some effort here discussing intricacies associated with both acute and chronic neuroinflammation before addressing the subject of microglial senescence. The idea of microglial senescence in the context of aging-r
TREM2 deficiency delays postnatal microglial maturation and synaptic pruning, leading to anxiety-like behaviors.
Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy.
Dual Role of Microglial TREM2 in Neuronal Degeneration and Regeneration After Axotomy
TREM2-mediated microglial phagocytosis of inhibitory synapses contributes to prolonged FS-induced epileptogenesis
A scalable human-zebrafish xenotransplantation model reveals gastrosome-mediated processing of dying neurons by human microglia
Evidence against (18)
Microglia-Mediated Neuroinflammation: A Potential Target for the Treatment of Cardiovascular Diseases.
Microglia are tissue-resident macrophages of the central nervous system (CNS). In the CNS, microglia play an important role in the monitoring and intervention of synaptic and neuron-level activities. Interventions targeting microglia have been shown to improve the prognosis of various neurological diseases. Recently, studies have observed the activation of microglia in different cardiovascular diseases. In addition, different approaches that regulate the activity of microglia have been shown to
TREM2, microglia, and Alzheimer's disease.
Triggering receptor expressed on myeloid cells 2 (TREM2) has been suggested to play a crucial role in Alzheimer's disease (AD) pathogenesis, as revealed by genome-wide association studies (GWAS). Since then, rapidly increasing literature related to TREM2 has focused on elucidating its role in AD pathology. In this review, we summarize our understanding of TREM2 biology, explore TREM2 functions in microglia, address the multiple mechanisms of TREM2 in AD, and raise key questions for further inves
Microglia states and nomenclature: A field at its crossroads.
Microglial research has advanced considerably in recent decades yet has been constrained by a rolling series of dichotomies such as "resting versus activated" and "M1 versus M2." This dualistic classification of good or bad microglia is inconsistent with the wide repertoire of microglial states and functions in development, plasticity, aging, and diseases that were elucidated in recent years. New designations continuously arising in an attempt to describe the different microglial states, notably
TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy.
Variants in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) were recently found to increase the risk for developing Alzheimer's disease (AD). In the brain, TREM2 is predominately expressed on microglia, and its association with AD adds to increasing evidence implicating a role for the innate immune system in AD initiation and progression. Thus far, studies have found
Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology.
Loss-of-function TREM2 mutations strongly increase Alzheimer's disease (AD) risk. Trem2 deletion has revealed protective Trem2 functions in preclinical models of β-amyloidosis, a prominent feature of pre-diagnosis AD stages. How TREM2 influences later AD stages characterized by tau-mediated neurodegeneration is unclear. To understand Trem2 function in the context of both β-amyloid and tau patholog
SYK coordinates neuroprotective microglial responses in neurodegenerative disease.
Recent studies have begun to reveal critical roles for the brain's professional phagocytes, microglia, and their receptors in the control of neurotoxic amyloid beta (Aβ) and myelin debris accumulation in neurodegenerative disease. However, the critical intracellular molecules that orchestrate neuroprotective functions of microglia remain poorly understood. In our studies, we find that targeted del
Cognitive enhancement and neuroprotective effects of OABL, a sesquiterpene lactone in 5xFAD Alzheimer's disease mice model.
Alzheimer's disease (AD) is a neurodegenerative disease in which oxidative stress and neuroinflammation were demonstrated to be associated with neuronal loss and cognitive deficits. However, there are still no specific treatments that can prevent the progression of AD. In this study, a screening of anti-inflammatory hits from 4207 natural compounds of two different molecular libraries indicated 1,
Glial reactivity correlates with synaptic dysfunction across aging and Alzheimer's disease.
Previous studies suggest glial and neuronal changes may trigger synaptic dysfunction in Alzheimer's disease (AD), but the link between their markers and synaptic abnormalities in the living brain remains unclear. We investigated the association between glial reactivity and synaptic dysfunction biomarkers in cerebrospinal fluid (CSF) from 478 individuals in cognitively unimpaired (CU) and cognitive
Sulfatide deficiency-induced astrogliosis and myelin lipid dyshomeostasis are independent of TREM2-mediated microglial activation.
Disrupted lipid homeostasis and neuroinflammation often co-exist in neurodegenerative disorders, including Alzheimer's disease (AD). However, the intrinsic connection and causal relationship between these deficits remain elusive. Our previous studies show that the loss of sulfatide (ST), a class of myelin-enriched lipids, causes AD-like neuroinflammatory responses, cognitive impairment, bladder en
cGAS-STING drives ageing-related inflammation and neurodegeneration.
Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease
Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes.
Microglia, the resident immune cells of the brain, rapidly change states in response to their environment, but we lack molecular and functional signatures of different microglial populations. Here, we analyzed the RNA expression patterns of more than 76,000 individual microglia in mice during development, in old age, and after brain injury. Our analysis uncovered at least nine transcriptionally di
Lectins and neurodegeneration: A glycobiologist's perspective.
1. Adv Clin Exp Med. 2025 May;34(5):673-679. doi: 10.17219/acem/204107. Lectins and neurodegeneration: A glycobiologist's perspective. Olejnik B(1), Ferens-Sieczkowska M(1). Author information: (1)Department of Biochemistry and Immunochemistry, Wroclaw Medical University, Poland. Neurodegenerative diseases, including Alzheimer's and Parkinson's disease, affect an increasing number of people in aging societies, dramatically reducing the quality of life of those affected. Hence, intensive research efforts are aimed at understanding the molecular mechanisms of the disease progress, with the hope for developing effective therapeutic strategies. The progress of neurodegenerative diseases is associated with a complex activity of the immune system in the brain tissue. Carbohydrate-bind
Effect of aging on biomarkers and clinical profile in Parkinson's disease.
1. J Neurol. 2025 Sep 24;272(10):651. doi: 10.1007/s00415-025-13384-7. Effect of aging on biomarkers and clinical profile in Parkinson's disease. Di Lazzaro G(1)(2), Paolini Paoletti F(3), Bellomo G(3), Schirinzi T(4), Grillo P(5)(6), Giuffrè GM(7)(8), Petracca M(7)(8), Picca A(7)(9), Mercuri NB(4), Parnetti L(3), Calabresi P(7)(8), Bentivoglio AR(7)(8). Author information: (1)Neurology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Agostino Gemelli 8, 00168, Rome, Italy. giulia.dilazzaro@policlinicogemelli.it. (2)Università Cattolica del Sacro Cuore, Rome, Italy. giulia.dilazzaro@policlinicogemelli.it. (3)Section of Neurology, Department of Medicine and Surgery, University Hospital of Perugia, Perugia, Italy. (4)Neurology Unit, Department of Systems Medi
Regulation of TREM2 expression by transcription factor YY1 and its protective effect against Alzheimer's disease.
1. J Biol Chem. 2023 May;299(5):104688. doi: 10.1016/j.jbc.2023.104688. Epub 2023 Apr 11. Regulation of TREM2 expression by transcription factor YY1 and its protective effect against Alzheimer's disease. Lu Y(1), Huang X(1), Liang W(1), Li Y(1), Xing M(2), Pan W(2), Zhang Y(1), Wang Z(3), Song W(4). Author information: (1)The National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical University, Beijing, China. (2)Zhejiang Provincial Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Wenzhou Kangning Hospital, Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Wenzhou Medical University, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou,
Microglia in Brain Aging and Age-Related Diseases: Friends or Foes?
1. Int J Mol Sci. 2025 Nov 27;26(23):11494. doi: 10.3390/ijms262311494. Microglia in Brain Aging and Age-Related Diseases: Friends or Foes? Ishikawa K(1), Fujikawa R(1), Okita K(1), Kimura F(1), Watanabe T(1), Katsurabayashi S(1), Iwasaki K(1). Author information: (1)Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. With the global rise in population aging, establishing effective strategies for the prevention and treatment of age-related neurodegenerative diseases, as well as their prodromal stage of cognitive frailty, has become an urgent challenge. Recent studies have revealed that the neural basis of both frailty and age-related disorders is closely associated with chronic neuroinflammat
Rejuvenating aged microglia by p16(ink4a)-siRNA-loaded nanoparticles increases amyloid-β clearance in animal models of Alzheimer's disease.
1. Mol Neurodegener. 2024 Mar 16;19(1):25. doi: 10.1186/s13024-024-00715-x. Rejuvenating aged microglia by p16(ink4a)-siRNA-loaded nanoparticles increases amyloid-β clearance in animal models of Alzheimer's disease. Shin HJ(1)(2), Kim IS(3)(4), Choi SG(1)(2), Lee K(1)(3)(5), Park H(1)(3), Shin J(1)(3), Kim D(1), Beom J(5), Yi YY(6), Gupta DP(7), Song GJ(7)(8), Chung WS(9), Lee CJ(10)(11), Kim DW(12)(13)(14)(15). Author information: (1)Department of Anatomy and Cell Biology, Chungnam National University College of Medicine, Daejeon, Republic of Korea. (2)Brain Research Institute, Chungnam National University College of Medicine, Daejeon, Republic of Korea. (3)Department of Medical Science, Chungnam National University College of Medicine, Daejeon, Republic of Korea. (4)Department o
Microglial Replacement Reverses Age-Associated Epigenetic Modifications Despite Accelerating Epigenetic Age.
1. Aging Dis. 2025 Oct 22. doi: 10.14336/AD.2025.1066. Online ahead of print. Microglial Replacement Reverses Age-Associated Epigenetic Modifications Despite Accelerating Epigenetic Age. Arbaizar-Rovirosa M(1)(2), Pérez RF(3), Peñarroya A(4)(5)(6)(7), Gallizioli M(1), Fraga MF(8)(4)(5)(9)(10), Planas AM(1)(2). Author information: (1)Cerebrovascular Research Laboratory, Instituto de Investigaciones. (2)Biomédicas de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. (3)Departamento de Bioquímica y Biología Molecular, Facultad de Veterinaria, Universidad Complutense de Madrid, Madrid, Spain. (4)Cancer Epigenetics and Nanomedicine Laboratory, Centro de Investi
Microglial aging in the healthy CNS: phenotypes, drivers, and rejuvenation.
1. Front Cell Neurosci. 2013 Mar 13;7:22. doi: 10.3389/fncel.2013.00022. eCollection 2013. Microglial aging in the healthy CNS: phenotypes, drivers, and rejuvenation. Wong WT(1). Author information: (1)Unit on Neuron-Glia Interactions in Retinal Disease, National Eye Institute, National Institutes of Health Bethesda, MD, USA. Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and age-related macular degeneration (AMD), share two characteristics in common: (1) a disease prevalence that increases markedly with advancing age, and (2) neuroinflammatory changes in which microglia, the primary resident immune cell of the CNS, feature prominently. These characteristics have led to the hypothesis that pathogenic mechanisms underlying age-related neurodegenerati
Evidence matrix
Supporting
- Sleep deprivation exacerbates microglial reactivity and Aβ deposition in a TREM2-dependent manner in mice. PMID:37099634 · 2023 · Sci Transl Med
- Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease. PMID:31932797 · 2020 · Nat Med
- TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways. PMID:36306735 · 2022 · Cell
- TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease. PMID:28802038 · 2017 · Cell
- Explores genetic variations linked to neurodegenerative disease proteins, potentially supporting the TREM2-dependent senescence hypothesis. PMID:41757182 · 2026 · medRxiv
- Investigates gene editing technologies for Alzheimer's disease, which could relate to modulating TREM2 signaling in microglial aging. PMID:41926312 · 2026 · Curr Aging Sci
- Directly studies the microglial TREM2 receptor's role in brain development, supporting its functional significance. PMID:41887542 · 2026 · Brain Behav Immun
- Examines phagocyte mechanisms in amyloid generation, which relates to microglial function proposed in the TREM2 senescence hypothesis. PMID:41770935 · 2026 · Proc Natl Acad Sci U S A
- Explores microglial neuroprotective responses, which aligns with TREM2 signaling mechanisms. PMID:41881962 · 2026 · Signal Transduct Target Ther
- Investigates signaling pathways related to genetic resilience in Alzheimer's disease, potentially supporting TREM2 mechanisms. PMID:41888907 · 2026 · Mol Neurodegener
- Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model. PMID:39353433 · 2024 · Neuron
- Microglia in neurodegeneration. PMID:30258234 · 2018 · Nat Neurosci
- TREM2 receptor protects against complement-mediated synaptic loss by binding to complement C1q during neurodegeneration. PMID:37442133 · 2023 · Immunity
- TREM2 and sTREM2 in Alzheimer's disease: from mechanisms to therapies. PMID:40247363 · 2025 · Mol Neurodegener
- Soluble TREM2 ameliorates tau phosphorylation and cognitive deficits through activating transgelin-2 in Alzheimer's disease. PMID:37865646 · 2023 · Nat Commun
- Preclinical and first-in-human evaluation of AL002, a novel TREM2 agonistic antibody for Alzheimer's disease. PMID:39444037 · 2024 · Alzheimers Res Ther
- Identification of senescent, TREM2-expressing microglia in aging and Alzheimer's disease model mouse brain. PMID:38637622 · 2024 · Nat Neurosci
- White matter aging drives microglial diversity. PMID:33606969 · 2021 · Neuron
- Effects of Fisetin Treatment on Cellular Senescence of Various Tissues and Organs of Old Sheep. PMID:37627641 · 2023 · Antioxidants (Basel)
- Roflumilast Attenuates Microglial Senescence and Retinal Inflammatory Neurodegeneration Post Retinal Ischemia Reperfusion Injury Through Inhibiting NLRP3 Inflammasome. PMID:39446353 · 2024 · Invest Ophthalmol Vis Sci
- Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice. PMID:33470505 · 2021 · Aging Cell
- Cisplatin and methotrexate induce brain microvascular endothelial and microglial senescence in mouse models of chemotherapy-associated cognitive impairment. PMID:39976845 · 2025 · Geroscience
- Prematurely Aged Human Microglia Exhibit Impaired Stress Response and Defective Nucleocytoplasmic Shuttling of ALS Associated FUS. PMID:40970514 · 2025 · Aging Cell
- Disentangling causality in brain aging: The complex interplay between glial senescence, neuroinflammation, and neurodegeneration. PMID:41871753 · 2026 · Exp Neurol
- A tetravalent TREM2 agonistic antibody reduced amyloid pathology in a mouse model of Alzheimer's disease. PMID:36070367 · 2022 · Sci Transl Med
- Adult-onset CNS myelin sulfatide deficiency is sufficient to cause Alzheimer's disease-like neuroinflammation and cognitive impairment. PMID:34526055 · 2021 · Mol Neurodegener
- Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic. PMID:34450028 · 2021 · Cell
- CD300f immune receptor contributes to healthy aging by regulating inflammaging, metabolism, and cognitive decline. PMID:37864797 · 2023 · Cell Rep
- Brain aging mechanisms with mechanical manifestations. PMID:34600936 · 2021 · Mech Ageing Dev
- Effect of peripheral cellular senescence on brain aging and cognitive decline. PMID:36959691 · 2023 · Aging Cell
- Microglial senescence. PMID:24047521 · 2013 · CNS Neurol Disord Drug Targets
- TREM2 deficiency delays postnatal microglial maturation and synaptic pruning, leading to anxiety-like behaviors. PMID:41930604 · 2026 · J Alzheimers Dis
- Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy. PMID:20301376 · 1993
- Dual Role of Microglial TREM2 in Neuronal Degeneration and Regeneration After Axotomy PMID:41963086 · 2026 · J Neurosci
- TREM2-mediated microglial phagocytosis of inhibitory synapses contributes to prolonged FS-induced epileptogenesis PMID:41965330 · 2026 · Cell Death Discov
- A scalable human-zebrafish xenotransplantation model reveals gastrosome-mediated processing of dying neurons by human microglia PMID:41957412 · 2026 · Commun Biol
Contradicting
- Microglia-Mediated Neuroinflammation: A Potential Target for the Treatment of Cardiovascular Diseases. PMID:35642214 · 2022 · J Inflamm Res
- TREM2, microglia, and Alzheimer's disease. PMID:33516818 · 2021 · Mech Ageing Dev
- Microglia states and nomenclature: A field at its crossroads. PMID:36327895 · 2022 · Neuron
- TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. PMID:29073081 · 2017 · Proc Natl Acad Sci U S A
- Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology. PMID:33675684 · 2021 · Neuron
- SYK coordinates neuroprotective microglial responses in neurodegenerative disease. PMID:36257314 · 2022 · Cell
- Cognitive enhancement and neuroprotective effects of OABL, a sesquiterpene lactone in 5xFAD Alzheimer's disease mice model. PMID:35026701 · 2022 · Redox Biol
- Glial reactivity correlates with synaptic dysfunction across aging and Alzheimer's disease. PMID:40593718 · 2025 · Nat Commun
- Sulfatide deficiency-induced astrogliosis and myelin lipid dyshomeostasis are independent of TREM2-mediated microglial activation. PMID:41513633 · 2026 · Nat Commun
- cGAS-STING drives ageing-related inflammation and neurodegeneration. PMID:37532932 · 2023 · Nature
- Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes. PMID:30471926 · 2019 · Immunity
- Lectins and neurodegeneration: A glycobiologist's perspective. PMID:40405515 · 2025 · Adv Clin Exp Med
- Effect of aging on biomarkers and clinical profile in Parkinson's disease. PMID:40991070 · 2025 · J Neurol
- Regulation of TREM2 expression by transcription factor YY1 and its protective effect against Alzheimer's disease. PMID:37044212 · 2023 · J Biol Chem
- Microglia in Brain Aging and Age-Related Diseases: Friends or Foes? PMID:41373648 · 2025 · Int J Mol Sci
- Rejuvenating aged microglia by p16(ink4a)-siRNA-loaded nanoparticles increases amyloid-β clearance in animal models of Alzheimer's disease. PMID:38493185 · 2024 · Mol Neurodegener
- Microglial Replacement Reverses Age-Associated Epigenetic Modifications Despite Accelerating Epigenetic Age. PMID:41135104 · 2025 · Aging Dis
- Microglial aging in the healthy CNS: phenotypes, drivers, and rejuvenation. PMID:23493481 · 2013 · Front Cell Neurosci
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Cite this hypothesis
Cite this hypothesis
etl-backfill (2026). Age-Dependent TREM2 Signaling Disrupts Astrocyte-Microglia Communication Leadin…. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/h-var-71ac892791
@misc{scidex_hypothesis_hvar71ac,
title = {Age-Dependent TREM2 Signaling Disrupts Astrocyte-Microglia Communication Leadin…},
author = {etl-backfill},
year = {2026},
howpublished = {SciDEX hypothesis},
url = {https://prism.scidex.ai/hypotheses/h-var-71ac892791},
note = {SciDEX artifact hypothesis:h-var-71ac892791}
}