Mechanistic description
Molecular Mechanism and Rationale
The proposed mechanism centers on the TREM2 (Triggering Receptor Expressed on Myeloid cells 2) and its adapter protein TYROBP (DNAX-activation protein 12, DAP12) signaling axis as a critical regulator of microglial homeostasis and cellular senescence resistance. TREM2 is a transmembrane glycoprotein receptor exclusively expressed on microglia within the central nervous system, where it functions as a pattern recognition receptor detecting phospholipids, lipoproteins, and cellular debris. Upon ligand binding, TREM2 undergoes conformational changes that promote clustering and recruitment of TYROBP, which contains immunoreceptor tyrosine-based activation motifs (ITAMs). Phosphorylation of TYROBP ITAMs by SRC family kinases triggers recruitment and activation of SYK kinase, initiating downstream signaling cascades essential for microglial survival, metabolic reprogramming, and stress resistance.
Under physiological conditions, activated TREM2/TYROBP signaling promotes PI3K/AKT pathway activation, leading to enhanced glucose metabolism, mitochondrial biogenesis, and DNA repair mechanisms. This signaling also activates the CREB-mediated transcriptional program that upregulates anti-senescence factors including SIRT1, FOXO transcription factors, and telomerase reverse transcriptase (TERT). Additionally, TREM2 signaling suppresses p53/p21 cell cycle checkpoint activation and reduces production of reactive oxygen species through enhanced antioxidant enzyme expression, including superoxide dismutase and catalase.
Loss-of-function TREM2 variants, including R47H, R62H, and frameshift mutations, fundamentally disrupt this protective signaling network. TREM2-deficient microglia exhibit compromised SYK activation, leading to reduced PI3K/AKT signaling and impaired mTORC1-dependent metabolic reprogramming. This creates a state of chronic energy stress characterized by mitochondrial dysfunction, increased oxidative damage, and accelerated telomere shortening. The resulting cellular stress triggers premature senescence through p53/p21 pathway activation and cyclin-dependent kinase inhibition, establishing a senescent phenotype characterized by cell cycle arrest, DNA damage accumulation, and acquisition of a pathological senescence-associated secretory phenotype (SASP).
Preclinical Evidence
Extensive preclinical evidence supports this mechanism across multiple model systems. In TREM2 knockout mice, aged microglia (>18 months) demonstrate significantly shortened telomeres (35-45% reduction in telomere length compared to wild-type controls) and increased DNA damage markers including γH2AX and 53BP1 foci formation. These cellular senescence markers are accompanied by a 60-70% reduction in proliferative capacity measured by BrdU incorporation and Ki67 staining. RNA sequencing analysis reveals upregulation of senescence-associated genes including p16INK4a, p21CIP1, and various SASP components.
The 5xFAD/TREM2 knockout mouse model demonstrates accelerated cognitive decline with spatial memory deficits appearing 2-3 months earlier than in 5xFAD mice alone, as measured by Morris water maze and Y-maze spontaneous alternation tests. Importantly, these mice exhibit a 40-60% reduction in beneficial microglial secretory factors including IL-33, lactate, and ATP in cerebrospinal fluid and brain tissue homogenates, while showing 3-4 fold increases in pro-inflammatory cytokines IL-1β, IL-6, and TNF-α.
Astrocyte dysfunction in these models is evidenced by reduced expression of neuroprotective markers including complement inhibitors CD55 and CD46 (50-65% reduction), anti-inflammatory mediators TGF-β and IL-10 (45-55% reduction), and metabolic support molecules including glutamine synthetase and BDNF (40-50% reduction). Functional assays demonstrate impaired astrocytic calcium signaling responses to neuronal activity and reduced glucose uptake capacity, indicating compromised neuron-astrocyte metabolic coupling.
Primary microglial cultures from TREM2 knockout mice subjected to oxidative stress show accelerated senescence onset with premature cell cycle exit and SASP acquisition occurring 48-72 hours earlier than wild-type controls. Co-culture experiments demonstrate that conditioned media from senescent TREM2-deficient microglia induces reactive astrocyte transformation with reduced expression of homeostatic markers ALDH1L1 and S100β, and increased expression of inflammatory markers including GFAP and complement C3.
Therapeutic Strategy and Delivery
The therapeutic approach targets multiple nodes within the TREM2-senescence-astrocyte dysfunction pathway using a combination of small molecule interventions and targeted biologics. The primary strategy employs senolytic compounds specifically targeting senescent microglia, including dasatinib and quercetin combination therapy, which selectively eliminate senescent cells through inhibition of anti-apoptotic pathways including BCL-2 and PI3K/AKT survival signaling.
Dasatinib, a multi-kinase inhibitor, demonstrates preferential toxicity toward senescent cells by targeting SRC family kinases and BCL-2 family proteins that senescent microglia rely upon for survival. Quercetin complements this mechanism by inhibiting PI3K/AKT signaling and reducing senescent cell anti-apoptotic defenses. The optimal dosing regimen involves intermittent administration (3 consecutive days every 2 weeks) to minimize effects on healthy cells while maximizing senescent cell clearance. Pharmacokinetic studies in rodent models demonstrate brain penetration with CSF:plasma ratios of 0.15-0.25 for dasatinib and 0.08-0.15 for quercetin following oral administration.
Complementary therapeutic modalities include TREM2 agonist antibodies designed to enhance residual TREM2 function in heterozygous carriers or restore signaling through alternative pathways. These antibodies target the TREM2 extracellular domain to promote receptor clustering and enhanced TYROBP recruitment, potentially compensating for reduced receptor expression or impaired ligand binding in variant carriers.
Additionally, direct astrocyte support through intranasal delivery of IL-33 and metabolic cofactors aims to bypass disrupted microglia-astrocyte communication. IL-33 administration has demonstrated efficacy in restoring astrocytic complement inhibitor expression and anti-inflammatory mediator production in preclinical models, with intranasal delivery achieving therapeutic brain concentrations while minimizing systemic exposure.
Evidence for Disease Modification
Disease modification is evidenced through multiple biomarker and functional outcome measures that distinguish symptomatic treatment from pathological intervention. Primary biomarkers include cerebrospinal fluid measurements of microglial senescence markers (p16INK4a, SASP cytokines) and astrocyte dysfunction indicators (reduced GFAP, S100β, complement inhibitors). Successful treatment demonstrates 50-70% reduction in senescence markers accompanied by restoration of beneficial microglia-derived factors including IL-33 and lactate.
Neuroimaging biomarkers utilize advanced PET tracers targeting microglial activation states, with successful disease modification showing reduced binding of pro-inflammatory markers (TSPO) and increased binding of homeostatic microglial markers. Diffusion tensor imaging demonstrates preservation of white matter tract integrity, indicating maintained astrocyte-mediated myelination support and reduced neuroinflammation-induced demyelination.
Functional outcomes demonstrating disease modification include preservation of synaptic density measured through SV2A PET imaging and electrophysiological assessment of long-term potentiation and synaptic plasticity. Cognitive assessments focus on executive function and processing speed rather than memory alone, as these domains are most sensitive to microglia-astrocyte dysfunction and show early improvement with pathway restoration.
Crucially, amyloid PET imaging in treatment responders shows stabilization or reduction in plaque burden, indicating restored microglial clearance function and improved astrocyte-mediated amyloid containment. This contrasts with symptomatic treatments that may improve cognition temporarily without affecting underlying pathological processes.
Clinical Translation Considerations
Clinical translation requires careful patient stratification based on TREM2 variant status, age, and disease stage. Primary candidates include individuals with heterozygous TREM2 loss-of-function variants (R47H, R62H) who retain partial receptor function amenable to enhancement. Homozygous carriers represent a distinct population requiring more intensive intervention but with potentially greater treatment responses.
Trial design employs adaptive randomization based on baseline biomarker profiles, with primary endpoints focused on biomarker changes (CSF senescence markers, astrocyte function indicators) at 6-12 months, and cognitive outcomes as secondary endpoints at 18-24 months. The heterogeneous nature of TREM2 variants necessitates variant-specific efficacy analysis and potentially individualized dosing regimens.
Safety considerations center on senolytic therapy administration, which requires careful monitoring for cytopenias and infection risk due to transient immune cell depletion. The intermittent dosing regimen minimizes these risks while maintaining efficacy. TREM2 agonist antibodies require assessment for autoimmune reactions and potential enhancement of beneficial versus pathological microglial activation states.
Regulatory pathway follows the FDA’s accelerated approval framework for neurodegenerative diseases, with biomarker-based primary endpoints and post-marketing studies confirming clinical benefit. The mechanism’s specificity to TREM2 variants may qualify for orphan drug designation, facilitating regulatory interactions and development incentives.
Competitive landscape analysis reveals limited direct competitors targeting the microglial senescence pathway, providing strategic advantages for first-in-class positioning. Existing TREM2-targeting approaches focus primarily on receptor activation without addressing senescence mechanisms, representing a differentiated therapeutic strategy.
Future Directions and Combination Approaches
Future research directions expand the senescent microglia-astrocyte paradigm to other neurodegenerative diseases with microglial involvement, including Parkinson’s disease, frontotemporal dementia, and multiple sclerosis. Cross-disease validation would establish microglial senescence as a common pathological mechanism amenable to shared therapeutic approaches.
Combination therapy development focuses on integrating senolytic treatment with complementary neuroprotective strategies. Combination with tau-targeting therapies addresses downstream neuronal pathology that may persist despite restored microglia-astrocyte function. Similarly, combination with amyloid-targeting approaches may enhance plaque clearance through restored microglial function while providing direct anti-amyloid effects.
Advanced delivery strategies under development include targeted nanoparticle systems for selective senescent cell targeting and sustained-release formulations for optimized senolytic exposure. Brain-penetrant senolytic compounds with improved pharmacokinetic profiles represent priority medicinal chemistry objectives.
Personalized medicine applications involve developing companion diagnostics for identifying optimal treatment candidates based on microglial senescence burden and astrocyte dysfunction severity. This includes advanced imaging biomarkers and CSF proteomic signatures that predict treatment response and guide individualized dosing strategies.
Long-term prevention strategies explore early intervention in TREM2 variant carriers before significant senescence accumulation, potentially preventing neurodegeneration onset rather than treating established disease. This prophylactic approach requires longitudinal natural history studies to identify optimal intervention timing and biomarker-guided treatment initiation criteria, representing a paradigm shift toward prevention-based neurodegeneration management.
Mechanism / pathway
- TREM2/TYROBP
- TREM2 signaling → microglial senescence → astrocyte-microglia communication disruption
- 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). TREM2-Dependent Senescent Microglia Disrupt Astrocyte Communication Networks. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/h-var-42a172bc53
@misc{scidex_hypothesis_hvar42a1,
title = {TREM2-Dependent Senescent Microglia Disrupt Astrocyte Communication Networks},
author = {etl-backfill},
year = {2026},
howpublished = {SciDEX hypothesis},
url = {https://prism.scidex.ai/hypotheses/h-var-42a172bc53},
note = {SciDEX artifact hypothesis:h-var-42a172bc53}
}