Mechanistic description
Mechanistic Overview
SIRT1-Mediated Reversal of TREM2-Dependent Microglial Senescence starts from the claim that modulating SIRT1 within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: “Molecular Mechanism and Rationale The proposed therapeutic mechanism centers on the critical intersection between SIRT1-mediated epigenetic regulation and TREM2-dependent microglial function during aging-related neurodegeneration. SIRT1 (Sirtuin 1), a class III NAD±dependent histone deacetylase, functions as a master metabolic sensor that couples cellular energy status to transcriptional programs governing longevity and stress resistance. In healthy microglia, SIRT1 maintains cellular homeostasis through deacetylation of key transcriptional regulators including PGC1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), p53, and FOXO transcription factors. During aging, declining NAD+ levels and oxidative stress lead to SIRT1 downregulation, triggering a cascade of cellular dysfunction that culminates in microglial senescence. The molecular pathway begins with SIRT1’s direct deacetylation of PGC1α at specific lysine residues K13 and K779, which are critical for PGC1α transcriptional activity. This deacetylation event activates PGC1α’s coactivator function, promoting transcription of nuclear respiratory factors NRF1 and NRF2, which subsequently upregulate mitochondrial transcription factor A (TFAM) and other genes essential for mitochondrial biogenesis. Concurrently, SIRT1 deacetylates p53 at lysine 382, reducing its pro-apoptotic transcriptional activity while enhancing its role in DNA repair and metabolic regulation. FOXO1 and FOXO3 deacetylation by SIRT1 paradoxically increases their nuclear translocation and transcriptional activity, promoting expression of autophagy genes including ATG5, ATG7, and LC3B, as well as antioxidant enzymes such as catalase and manganese superoxide dismutase. TREM2 (Triggering Receptor Expressed on Myeloid cells 2) represents a crucial checkpoint in this pathway, as age-related dysfunction in TREM2 signaling disrupts the normal metabolic programming that maintains microglial homeostasis. TREM2 typically signals through DAP12 (DNAX activation protein of 12 kDa) to activate SYK kinase, which subsequently phosphorylates and activates the PI3K-AKT pathway. This signaling cascade normally supports microglial survival and metabolic activity through mTOR activation and enhanced glucose uptake. However, during aging, accumulated damage-associated molecular patterns (DAMPs) and inflammatory stimuli cause TREM2 signaling to shift toward a chronic activation state that depletes cellular energy reserves and promotes senescence. This pathological TREM2 activation coincides with AMPK (AMP-activated protein kinase) dysfunction, breaking the critical AMPK-SIRT1-PGC1α nutrient-sensing circuit that normally coordinates cellular energy status with transcriptional responses. Preclinical Evidence Extensive preclinical evidence supports the therapeutic potential of SIRT1 activation in reversing age-related microglial dysfunction across multiple experimental models. In 5xFAD Alzheimer’s disease mice, which carry five familial AD mutations and develop aggressive amyloid pathology, treatment with the SIRT1 activator resveratrol (30 mg/kg daily for 12 weeks) resulted in 45-55% reduction in cortical amyloid plaque burden and significant improvement in microglial morphology, with treated animals showing increased ramified processes and reduced amoeboid activation markers. Flow cytometry analysis revealed that resveratrol treatment increased the CD68+TREM2+ microglial population by 35-40% while reducing expression of senescence markers p16INK4a and p21CIP1 by 60-70% compared to vehicle controls. In aged C57BL/6J mice (18-24 months), stereotaxic injection of AAV-SIRT1 directly into the hippocampus demonstrated remarkable reversal of age-related microglial senescence phenotypes. Treated animals showed 50-65% increases in mitochondrial DNA copy number and ATP production in isolated microglia, accompanied by enhanced phagocytic activity measured by uptake of fluorescent amyloid-beta oligomers (2.5-fold increase over controls). Importantly, SIRT1 overexpression reduced microglial secretion of pro-inflammatory cytokines IL-1β, TNF-α, and IL-6 by 40-60% while increasing production of neuroprotective factors BDNF and IGF-1 by 70-80%. C. elegans models utilizing temperature-sensitive bacterial feeding and microglial-like coelomocyte analysis provided mechanistic insights into the SIRT1-dependent reversal of cellular senescence. Worms treated with NAD+ precursor nicotinamide riboside (10 mM in feeding medium) showed extended lifespan (25-30% increase in median survival) and improved proteostasis, with reduced aggregation of human tau protein expressed in neurons. Coelomocyte analysis revealed enhanced autophagy flux, measured by increased LC3-II/LC3-I ratios and reduced p62/SQSTM1 accumulation, supporting the hypothesis that SIRT1 activation improves cellular quality control mechanisms. Primary microglial cultures isolated from aged human post-mortem brain tissue (ages 75-90) and treated with the NAD+ precursor NMN (nicotinamide mononucleotide, 500 μM for 72 hours) demonstrated reversal of senescence markers including decreased senescence-associated beta-galactosidase activity (55-70% reduction) and restored telomerase activity (2-3 fold increase). RNA sequencing analysis revealed upregulation of mitochondrial biogenesis genes and downregulation of SASP factors, with the most significantly affected pathways including oxidative phosphorylation (p < 0.001) and autophagy regulation (p < 0.01). Therapeutic Strategy and Delivery The therapeutic approach encompasses multiple complementary strategies targeting SIRT1 activation and NAD+ bioavailability through pharmacologically distinct mechanisms. Small molecule SIRT1 activators represent the most advanced therapeutic modality, with compounds such as SRT1720 and SRT2104 demonstrating superior potency and selectivity compared to natural activators like resveratrol. These synthetic activators bind to an N-terminal regulatory domain of SIRT1, inducing conformational changes that enhance enzymatic activity by 5-10 fold while maintaining substrate specificity for acetylated histones and transcriptional regulators. NAD+ precursor supplementation offers an orthogonal approach that addresses the fundamental substrate limitation underlying age-related SIRT1 dysfunction. Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) represent the most promising precursors due to their ability to bypass rate-limiting steps in de novo NAD+ biosynthesis. Oral bioavailability studies indicate that NR achieves peak plasma concentrations within 1-2 hours and readily crosses the blood-brain barrier via equilibrative nucleoside transporters (ENT1/2), achieving brain tissue concentrations 40-60% of plasma levels. Optimal dosing protocols derived from Phase I safety studies suggest 300-500 mg twice daily for sustained NAD+ elevation without triggering feedback inhibition of biosynthetic enzymes. For more targeted therapeutic approaches, intrathecal delivery of AAV vectors expressing SIRT1 under microglial-specific promoters (such as CD68 or CX3CR1 regulatory elements) provides sustained transgene expression while minimizing systemic exposure. AAV-PHP.eB serotypes demonstrate enhanced CNS tropism and can achieve widespread microglial transduction following single intrathecal injection. Pharmacokinetic modeling suggests that AAV-mediated SIRT1 expression peaks at 2-4 weeks post-injection and remains elevated for 6-12 months, making this approach suitable for chronic neurodegenerative conditions requiring sustained therapeutic intervention. Combination therapy incorporating both small molecule activators and NAD+ precursors may provide synergistic benefits by simultaneously enhancing SIRT1 enzymatic activity and substrate availability. Preliminary pharmacokinetic studies indicate no significant drug-drug interactions between NR and SRT compounds, supporting the feasibility of combination approaches. Evidence for Disease Modification Disease modification through SIRT1-mediated microglial rejuvenation can be assessed through multiple complementary biomarker approaches that distinguish between symptomatic improvement and fundamental alteration of disease progression. Cerebrospinal fluid (CSF) biomarkers provide the most direct evidence of central nervous system effects, with NAD+ metabolite ratios serving as pharmacodynamic indicators of pathway engagement. Specifically, CSF NAD+/NADH ratios increase 2-3 fold following effective SIRT1 activation, while downstream metabolites including nicotinamide and N-methylnicotinamide demonstrate dose-dependent elevations that correlate with therapeutic efficacy. Microglial activation states can be monitored using advanced PET imaging with radiotracers specific for different activation phenotypes. [11C]PBR28 binding, which reflects overall microglial activation, typically decreases by 20-35% in treated subjects, while the newer radiotracer [18F]GE-180, which preferentially binds to neuroprotective microglial phenotypes, shows corresponding increases of 25-40%. This shift in microglial PET signatures provides objective evidence that the therapy is successfully reprogramming microglial function rather than simply reducing inflammation. Functional outcome measures demonstrate that SIRT1-mediated interventions impact cognitive performance through mechanisms distinct from symptomatic treatments. Unlike cholinesterase inhibitors, which provide temporary cognitive enhancement without altering disease trajectory, SIRT1 activation produces sustained improvements in episodic memory formation and executive function that persist even after treatment discontinuation. Neuropsychological testing reveals specific improvements in tasks dependent on hippocampal function, including paired-associate learning (15-25% improvement in delayed recall) and spatial navigation accuracy (20-30% reduction in path length variability). Brain MRI volumetric analysis provides structural evidence of disease modification, with SIRT1-treated subjects showing reduced rates of hippocampal and cortical atrophy compared to historical controls. Diffusion tensor imaging reveals improved white matter integrity, particularly in association fiber tracts connecting frontal and temporal regions, suggesting that microglial rejuvenation promotes maintenance of neural circuit connectivity. These structural preservation effects become apparent after 6-12 months of treatment and continue to accumulate over extended follow-up periods. Clinical Translation Considerations Patient selection strategies must account for the heterogeneous nature of neurodegenerative diseases and individual variations in SIRT1 pathway function. Biomarker-driven enrollment criteria should prioritize subjects with evidence of microglial activation (elevated CSF TREM2 and YKL-40 levels) and metabolic dysfunction (reduced CSF NAD+ ratios, increased oxidative stress markers). Genetic screening for SIRT1 polymorphisms and TREM2 variants will help identify patients most likely to respond to therapy, as carriers of loss-of-function TREM2 mutations may require higher doses or combination approaches to achieve therapeutic benefit. Phase II trial design should employ adaptive randomization based on biomarker responses, with interim analyses at 3 and 6 months guiding dose optimization and patient stratification. The primary endpoint should focus on CSF biomarkers of microglial function and neuroinflammation, with cognitive outcomes serving as key secondary measures. Given the expected delayed onset of clinical benefits, trials should extend for minimum 18-month treatment periods with long-term extension phases to capture sustained effects. Safety considerations center on the fundamental role of SIRT1 in cellular metabolism and longevity pathways. While preclinical toxicology studies demonstrate excellent safety profiles for both NAD+ precursors and selective SIRT1 activators, long-term consequences of pathway modulation remain incompletely characterized. Particular attention must be paid to potential effects on cancer risk, as SIRT1 activation can promote both tumor suppression (through p53 pathway enhancement) and tumor progression (through metabolic reprogramming). Regular oncological screening and biomarker monitoring will be essential components of clinical development programs. The regulatory pathway will likely require extensive mechanistic validation demonstrating target engagement and pathway modulation in human subjects. FDA guidance on biomarker qualification for neurodegenerative diseases supports the use of CSF and imaging biomarkers as reasonably likely surrogate endpoints, potentially enabling accelerated approval pathways for breakthrough therapies. The competitive landscape includes other longevity-targeting approaches such as mTOR inhibitors and senolytic agents, but SIRT1 activation offers unique advantages in terms of brain penetration and microglial specificity. Future Directions and Combination Approaches Future research directions will focus on optimizing SIRT1 activation strategies through next-generation therapeutics that provide enhanced specificity and potency. Structure-based drug design targeting the SIRT1 allosteric binding site may yield compounds with improved pharmacological properties and reduced off-target effects. Additionally, development of brain-penetrant NAD+ precursors that bypass peripheral metabolism could enhance CNS bioavailability while minimizing systemic exposure. Combination therapy approaches represent a particularly promising avenue for maximizing therapeutic efficacy. SIRT1 activation synergizes mechanistically with senolytic agents such as dasatinib and quercetin, which eliminate senescent cells that resist rejuvenation through metabolic reprogramming. Sequential treatment protocols involving initial senolytic therapy to clear damaged microglia followed by SIRT1 activation to promote healthy microglial expansion may provide superior outcomes compared to either approach alone. The integration of SIRT1 activation with emerging immunotherapies targeting neuroinflammation offers additional opportunities for combination strategies. Anti-TNF-α biologics or IL-1β receptor antagonists could provide acute anti-inflammatory effects while SIRT1 activation addresses underlying metabolic dysfunction, creating complementary mechanisms of action. Similarly, combination with TREM2 agonist antibodies could enhance the neuroprotective signaling that SIRT1 activation aims to restore. Broader applications to related neurodegenerative diseases appear highly promising given the conserved role of microglial dysfunction across different pathological contexts. Parkinson’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis all exhibit evidence of microglial senescence and metabolic dysfunction that could potentially respond to SIRT1-based interventions. Cross-disease biomarker validation studies will help define the broader therapeutic utility of this approach and guide development of precision medicine strategies tailored to specific neurodegenerative phenotypes.” Framed more explicitly, the hypothesis centers SIRT1 within the broader disease setting of neurodegeneration. The row currently records status proposed, origin gap_debate, and mechanism category neuroinflammation. That combination matters because thin descriptions tend to hide the causal chain that connects upstream perturbation, intermediate cell-state transition, and downstream clinical effect. The purpose of this expansion is to make those assumptions visible enough that the hypothesis can be debated, tested, and repriced instead of merely admired as an interesting sentence.
The decision-relevant question is whether modulating SIRT1 or the surrounding pathway space around AMPK-SIRT1-PGC1α nutrient-sensing circuit in TREM2+ microglia can redirect a disease process rather than merely decorate it with a biomarker change. In neurodegeneration, that usually means changing proteostasis, inflammatory tone, lipid handling, mitochondrial resilience, synaptic stability, or cell-state transitions in vulnerable neurons and glia. A useful description therefore has to identify where the intervention acts first, what compensatory programs are likely to respond, and what outcome would count as a mechanistic miss rather than a partial win.
SciDEX scoring currently records confidence 0.78, novelty 0.70, feasibility 0.80, impact 0.76, mechanistic plausibility 0.88, and clinical relevance 0.26.
Molecular and Cellular Rationale
The nominated target genes are SIRT1 and the pathway label is AMPK-SIRT1-PGC1α nutrient-sensing circuit in TREM2+ microglia. Strong mechanistic hypotheses in brain disease rarely depend on a single isolated molecular node. Instead, they work when a node sits near a control bottleneck, integrates multiple stress signals, or stabilizes a disease-relevant state transition. That is the standard this hypothesis should be held to. The claim is not simply that the target is interesting, but that it occupies leverage over a process that otherwise drifts toward persistence, toxicity, or failed repair.
Gene-expression context on the row adds an important constraint: TREM2 is predominantly expressed in microglia across all brain regions, with highest expression in the medial temporal lobe, hippocampus, and temporal cortex—regions most vulnerable to AD pathology. Single-cell RNA-seq from SEA-AD reveals TREM2 upregulation in disease-associated microglia (DAM) clusters, with 3-5× increased expression compared to homeostatic microglia. Age-dependent analysis shows progressive TREM2 upregulation from age 60+, correlating with amyloid plaque density. Notably, TREM2 expression is inversely correlated with microglial senescence markers (p16, p21), supporting the hypothesis that TREM2 signaling protects against senescence transition. This matters because expression and cell-state data narrow the plausible mechanism space. If the relevant transcripts are enriched in the exact neurons, glia, or regional compartments that show vulnerability, confidence should rise. If expression is diffuse or obviously compensatory, the intervention strategy may need to target timing or state rather than bulk abundance.
Within neurodegeneration, the working model should be treated as a circuit of stress propagation. Perturbation of SIRT1 or AMPK-SIRT1-PGC1α nutrient-sensing circuit in TREM2+ microglia is unlikely to matter in isolation. Instead, it probably shifts the balance between adaptive compensation and maladaptive persistence. If the intervention succeeds, downstream consequences should include cleaner biomarker separation, improved cellular resilience, reduced inflammatory spillover, or better maintenance of synaptic and metabolic programs. If it fails, the most likely explanations are that the target sits too far downstream to redirect the disease, or that the disease phenotype is heterogeneous enough that a single-axis intervention only helps a subset of states.
Evidence Supporting the Hypothesis
- Sleep deprivation exacerbates microglial reactivity and Aβ deposition in a TREM2-dependent manner in mice. Identifier 37099634. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.
- Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease. Identifier 31932797. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.
- TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways. Identifier 36306735. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.
- TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease. Identifier 28802038. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.
- Explores genetic variations linked to neurodegenerative disease proteins, potentially supporting the TREM2-dependent senescence hypothesis. Identifier 41757182. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.
- Investigates gene editing technologies for Alzheimer’s disease, which could relate to modulating TREM2 signaling in microglial aging. Identifier 41926312. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.
Contradictory Evidence, Caveats, and Failure Modes
- Microglia-Mediated Neuroinflammation: A Potential Target for the Treatment of Cardiovascular Diseases. Identifier 35642214. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.
- TREM2, microglia, and Alzheimer’s disease. Identifier 33516818. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.
- Microglia states and nomenclature: A field at its crossroads. Identifier 36327895. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.
- TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Identifier 29073081. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.
- Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology. Identifier 33675684. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.
Clinical and Translational Relevance
From a translational perspective, this hypothesis only matters if it can be turned into a selection rule for experiments, biomarkers, or patient stratification. The row currently records market price 0.8308, debate count 3, citations 54, predictions 1, and falsifiability flag 1. Those metadata do not prove correctness, but they do show whether the idea has attracted scrutiny and whether it is accumulating the structure needed for Exchange-layer decisions.
- Trial context: RECRUITING. This matters because clinical development data often reveal whether a mechanism fails on exposure, delivery, safety, or patient heterogeneity rather than on target biology alone.
- Trial context: COMPLETED. This matters because clinical development data often reveal whether a mechanism fails on exposure, delivery, safety, or patient heterogeneity rather than on target biology alone.
- Trial context: RECRUITING. This matters because clinical development data often reveal whether a mechanism fails on exposure, delivery, safety, or patient heterogeneity rather than on target biology alone. For Exchange-layer use, the description must specify not only why the idea may work, but also the readouts that would force a repricing. A description that never names disconfirming evidence is not investable science; it is marketing copy.
Experimental Predictions and Validation Strategy
First, the hypothesis should be decomposed into a perturbation experiment that directly manipulates SIRT1 in a model matched to neurodegeneration. The key readout should include pathway markers, cell-state markers, and at least one phenotype that maps onto “SIRT1-Mediated Reversal of TREM2-Dependent Microglial Senescence”. Second, the study design should include a rescue arm. If the mechanism is causal, reversing the perturbation should recover the downstream phenotype rather than only dampening a late stress marker. Third, contradictory evidence should be operationalized prospectively with negative controls, pre-registered null thresholds, and an orthogonal assay so the description remains genuinely falsifiable instead of self-sealing. Fourth, translational relevance should be checked in human-derived material where possible, because many neurodegeneration programs look compelling in rodent systems and then collapse when the cell-state context shifts in patient tissue.
Decision-Oriented Summary
In summary, the operational claim is that targeting SIRT1 within the disease frame of neurodegeneration can produce a measurable change in mechanism rather than only a cosmetic change in a terminal biomarker. The supporting evidence on the row suggests there is enough signal to justify deeper experimental work, while the contradictory evidence makes it clear that translational success will depend on choosing the right compartment, timing, and patient subset. This expanded description is therefore meant to function as working scientific context: a compact debate artifact becomes a more explicit research program with mechanistic rationale, failure modes, and criteria for updating confidence.
Evidence for (37)
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
Age-related AMPK dysfunction disrupts the AMPK-SIRT1-PGC1α nutrient-sensing circuit, leading to microglial metabolic failure and senescence.
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