bims-microg 2024-10-27 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2024–10–27
23 papers selected by
Marcus Karlstetter, Universität zu Köln

Preclinical and first-in-human evaluation of AL002, a novel TREM2 agonistic antibody for Alzheimer's disease.
Long-term reprogramming of primed microglia after moderate inhibition of CSF1R signaling.
Microglia-mediated neuroinflammation in traumatic brain injury: a review.
Microglia regulate cortical remyelination via TNFR1-dependent phenotypic polarization.
Uptake of alpha-synuclein preformed fibrils is suppressed by inflammation and induces an aberrant phenotype in human microglia.
Remyelination protects neurons from DLK-mediated neurodegeneration.
RIP1 inhibition protects retinal ganglion cells in glaucoma models of ocular injury.
PET imaging of microglia in Alzheimer's disease using copper-64 labeled TREM2 antibodies.
Microglia overexpressing brain-derived neurotrophic factor promote vascular repair and functional recovery in mice after spinal cord injury.
Microglia ameliorate delirium-like phenotypes in a murine model of acute ventilator-induced lung injury.
Roflumilast Attenuates Microglial Senescence and Retinal Inflammatory Neurodegeneration Post Retinal Ischemia Reperfusion Injury Through Inhibiting NLRP3 Inflammasome.
Loss of CLN3 in microglia leads to impaired lipid metabolism and myelin turnover.
Three-dimensional view of microglia-amyloid plaque interactions.
The deficient CLEC5A ameliorates the behavioral and pathological deficits via the microglial Aβ clearance in Alzheimer's disease mouse model.
METTL14 Promotes Ischemic Stroke-induced Brain Injury by Stabilizing HDAC3 Expression in an m6A-IGF2BP3 Mechanism.
Microglial Melatonin Receptor 1 Degrades Pathological Alpha-Synuclein Through Activating LC3-Associated Phagocytosis In Vitro.
Age at Injury as a Modifier of Preclinical TBI Behavioral, Neuropathological, and Inflammatory Outcomes.
The antipsychotic chlorpromazine reduces neuroinflammation by inhibiting microglial voltage-gated potassium channels.
Interaction between subventricular zone microglia and neural stem cells impacts the neurogenic response in a mouse model of cortical ischemic stroke.
Emerging role of microglia in inter-cellular transmission of α-synuclein in Parkinson's disease.
WIF-1 contributes to lupus-induced neuropsychological deficits via the CRYAB/STAT4-SHH axis.
SARS-CoV-2 spike S1 protein induces microglial NLRP3-dependent neuroinflammation and cognitive impairment in mice.
Senolytic therapy preserves blood-brain barrier integrity and promotes microglia homeostasis in a tauopathy model.

Alzheimers Res Ther. 2024 Oct 23. 16(1): 235

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

Hua Long, Adam Simmons, Arthur Mayorga, Brady Burgess, Tuan Nguyen, Balasubrahmanyam Budda, Anna Rychkova, Herve Rhinn, Ilaria Tassi, Michael Ward, Felix Yeh, Tina Schwabe, Robert Paul, Sara Kenkare-Mitra, Arnon Rosenthal.

   BACKGROUND: 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 inflammatory signaling. Thus, TREM2 activation has potential to alter the progression of AD. AL002 is an investigational, engineered, humanized monoclonal immunoglobulin G1 (IgG1) antibody designed to target TREM2. In AD mouse models, an AL002 murine variant has been previously shown to induce microglial proliferation and reduce filamentous Aβ plaques and neurite dystrophy.
METHODS: Preclinical studies assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of AL002 in cynomolgus monkeys. INVOKE-1 (NCT03635047) was a first-in-human phase 1, randomized, placebo-controlled, double-blind study assessing the safety, tolerability, PK, and PD of AL002 administered as single ascending doses (SAD) in healthy volunteers.
RESULTS: In cynomolgus monkeys, weekly intravenous injections of AL002 for 4 weeks were well tolerated, dose-dependently decreased soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF) and total TREM2 in hippocampus and frontal cortex, and increased biomarkers of TREM2 signaling in CSF and brain. In the phase 1 study of 64 healthy volunteers, a single intravenous infusion of AL002 demonstrated brain target engagement based on a dose-dependent reduction of sTREM2 in CSF and parallel increases in biomarkers of TREM2 signaling and microglia recruitment. Single-dose AL002 showed central nervous system penetrance and was well tolerated, with no treatment-related serious adverse events over 12 weeks.
CONCLUSIONS: These findings support the continued clinical development of AL002 for AD and other neurodegenerative diseases in which TREM2 activation may be beneficial. AL002 is currently being tested in a phase 2, randomized, double-blind, placebo-controlled study in early AD.
TRIAL REGISTRATION: Clinicaltrials.gov, NCT03635047. Registered on August 15, 2018, https://www.
CLINICALTRIALS: gov/study/NCT03635047 .

Keywords:  Alzheimer’s disease; Biomarkers; Microglia; Phase 1 clinical trial; TREM2

DOI:  https://doi.org/10.1186/s13195-024-01599-1
Glia. 2024 Oct 24.

Long-term reprogramming of primed microglia after moderate inhibition of CSF1R signaling.

Ana León-Rodríguez, Jesús M Grondona, Sonia Marín-Wong, Manuel F López-Aranda, María D López-Ávalos.

  In acute neuroinflammation, microglia activate transiently, and return to a resting state later on. However, they may retain immune memory of such event, namely priming. Primed microglia are more sensitive to new stimuli and develop exacerbated responses, representing a risk factor for neurological disorders with an inflammatory component. Strategies to control the hyperactivation of microglia are, hence, of great interest. The receptor for colony stimulating factor 1 (CSF1R), expressed in myeloid cells, is essential for microglia viability, so its blockade with specific inhibitors (e.g. PLX5622) results in significant depletion of microglial population. Interestingly, upon inhibitor withdrawal, new naïve microglia repopulate the brain. Depletion-repopulation has been proposed as a strategy to reprogram microglia. However, substantial elimination of microglia is inadvisable in human therapy. To overcome such drawback, we aimed to reprogram long-term primed microglia by CSF1R partial inhibition. Microglial priming was induced in mice by acute neuroinflammation, provoked by intracerebroventricular injection of neuraminidase. After 3-weeks recovery, low-dose PLX5622 treatment was administrated for 12 days, followed by a withdrawal period of 7 weeks. Twelve hours before euthanasia, mice received a peripheral lipopolysaccharide (LPS) immune challenge, and the subsequent microglial inflammatory response was evaluated. PLX5622 provoked a 40%-50% decrease in microglial population, but basal levels were restored 7 weeks later. In the brain regions studied, hippocampus and hypothalamus, LPS induced enhanced microgliosis and inflammatory activation in neuraminidase-injected mice, while PLX5622 treatment prevented these changes. Our results suggest that PLX5622 used at low doses reverts microglial priming and, remarkably, prevents broad microglial depletion.

Keywords:  CSF1R; PLX5622; microglia; neuroinflammation; priming

DOI:  https://doi.org/10.1002/glia.24627
Mol Biol Rep. 2024 Oct 19. 51(1): 1073

Microglia-mediated neuroinflammation in traumatic brain injury: a review.

Oyovwi Mega Obukohwo, Oyelere Abosede Oreoluwa, Udi Onoriode Andrew, Ugwuishi Emeka Williams.

  Traumatic brain injury (TBI) is a leading cause of disability worldwide, characterized by a complex interplay of primary and secondary injury mechanisms. Microglia, the resident immune cells of the central nervous system, play a crucial role in the inflammatory response following TBI. To review the current understanding of microglia-mediated neuroinflammation in TBI, exploring its dual nature as a protective and detrimental process. A comprehensive literature review was conducted using databases such as PubMed, Scopus, and Google Scholar. Relevant studies investigating the role of microglia in TBI were included. In the early stages of TBI, microglia exhibit a protective response, releasing cytokines and chemokines to promote neuronal survival and tissue repair. However, prolonged or excessive microglial activation can lead to neurotoxicity and exacerbate secondary injury. Microglia-mediated neuroinflammation involves complex signaling pathways, including Toll-like receptors, purinergic receptors, and the complement system. Microglia-mediated neuroinflammation in TBI is a double-edged sword. While acute microglial activation can promote repair, chronic or excessive inflammation contributes to neuronal damage and functional deficits. Understanding the temporal and molecular dynamics of microglial responses is crucial for developing therapeutic strategies to modulate neuroinflammation and improve outcomes after TBI.

Keywords:  Microglia; Neuroinflammation; Toll-like receptors; Traumatic brain injury

DOI:  https://doi.org/10.1007/s11033-024-09995-4
Cell Rep. 2024 Oct 23. pii: S2211-1247(24)01245-2. [Epub ahead of print]43(11): 114894

Microglia regulate cortical remyelination via TNFR1-dependent phenotypic polarization.

Athena Boutou, Ilias Roufagalas, Katerina Politopoulou, Spyros Tastsoglou, Maya Abouzeid, Giorgos Skoufos, Laia Verdu de Juan, Jeong Hun Ko, Vasiliki Kyrargyri, Artemis G Hatzigeorgiou, Christopher J Barnum, Raymond J Tesi, Jan Bauer, Hans Lassmann, Michael R Johnson, Lesley Probert.

  Microglia are strongly implicated in demyelinating neurodegenerative diseases with increasing evidence for roles in protection and healing, but the mechanisms that control CNS remyelination are poorly understood. Here, we show that microglia-specific deletion of tumor necrosis factor receptor 1 (TNFR1) and pharmacological inhibition of soluble TNF (solTNF) or downstream interleukin-1 receptor (IL-1R) allow maturation of highly activated disease-associated microglia with increased size and myelin phagocytosis capacity that accelerate cortical remyelination and motor recovery. Single-cell transcriptomic analysis of cortex at disease onset reveals that solTNF inhibition enhances reparative IL-10-responsive while preventing damaging IL-1-related signatures of disease-associated microglia. Longitudinal brain transcriptome analysis through disease reveals earlier recovery upon therapeutic loss of microglia TNFR1. The functional relevance of microglia inflammatory polarization pathways for disease is validated in vivo. Furthermore, disease-state microglia producing downstream IL-1/IL-18/caspase-11 targets are identified in human demyelinating lesions. Overall, redirecting disease microglia polarization by targeting cytokines is a potential approach for improving CNS repair in demyelinating disorders.

Keywords:  CP: Immunology; CP: Neuroscience; DAM; IL-1; TNF; demyelination; microglia; multiple sclerosis; neuroinflammation; neuromyelitis optica; oligodendrocyte differentiation; remyelination

DOI:  https://doi.org/10.1016/j.celrep.2024.114894
Glia. 2024 Oct 22.

Uptake of alpha-synuclein preformed fibrils is suppressed by inflammation and induces an aberrant phenotype in human microglia.

Jonna Niskanen, Sanni Peltonen, Sohvi Ohtonen, Mohammad Feroze Fazaludeen, Kelvin C Luk, Luca Giudice, Jari Koistinaho, Tarja Malm, Gundars Goldsteins, Katrina Albert, Šárka Lehtonen.

  Microglia are brain resident immune cells that maintain proteostasis and cellular homeostasis. Recent findings suggest that microglia dysfunction could contribute to the pathogenesis of Parkinson's disease (PD). One of the hallmarks of PD is the aggregation and accumulation of alpha-synuclein (αSyn) into Lewy bodies inside nerve cells. Microglia may worsen the neuronal microenvironment by persistent inflammation, resulting in deficient clearing of aggregated αSyn. To model microglial behavior in PD, we utilized human induced pluripotent stem cells to generate functionally active microglia. We studied the microglial uptake of alpha-synuclein preformed fibrils (PFFs) and the effect of pro-inflammatory stimulation by interferon gamma. We demonstrate that combined exposure disrupts the phagosome maturation pathway while inflammatory stimuli suppress chaperone mediated autophagy and mitochondrial function. Furthermore, inflammatory stimulation impairs PFF uptake in microglia and increases cytokine production. Moreover, excessive PFF uptake by microglia results in induction of inducible nitric oxide synthase. Taken together, we demonstrate that this model is valuable for investigating the behavior of microglia in PD and provide new insights on how human microglia process aggregated αSyn.

Keywords:  Parkinson's disease; alpha‐synuclein preformed fibrils; autophagy; hiPSCs; microglia; phagocytosis

DOI:  https://doi.org/10.1002/glia.24626
Nat Commun. 2024 Oct 23. 15(1): 9148

Remyelination protects neurons from DLK-mediated neurodegeneration.

Greg J Duncan, Sam D Ingram, Katie Emberley, Jo Hill, Christian Cordano, Ahmed Abdelhak, Michael McCane, Jennifer E Jenks, Nora Jabassini, Kirtana Ananth, Skylar J Ferrara, Brittany Stedelin, Benjamin Sivyer, Sue A Aicher, Thomas S Scanlan, Trent A Watkins, Anusha Mishra, Jonathan W Nelson, Ari J Green, Ben Emery.

Chronic demyelination and oligodendrocyte loss deprive neurons of crucial support. It is the degeneration of neurons and their connections that drives progressive disability in demyelinating disease. However, whether chronic demyelination triggers neurodegeneration and how it may do so remain unclear. We characterize two genetic mouse models of inducible demyelination, one distinguished by effective remyelination and the other by remyelination failure and chronic demyelination. While both demyelinating lines feature axonal damage, mice with blocked remyelination have elevated neuronal apoptosis and altered microglial inflammation, whereas mice with efficient remyelination do not feature neuronal apoptosis and have improved functional recovery. Remyelination incapable mice show increased activation of kinases downstream of dual leucine zipper kinase (DLK) and phosphorylation of c-Jun in neuronal nuclei. Pharmacological inhibition or genetic disruption of DLK block c-Jun phosphorylation and the apoptosis of demyelinated neurons. Together, we demonstrate that remyelination is associated with neuroprotection and identify DLK inhibition as protective strategy for chronically demyelinated neurons.

DOI: https://doi.org/10.1038/s41467-024-53429-5
Cell Death Differ. 2024 Oct 24.

RIP1 inhibition protects retinal ganglion cells in glaucoma models of ocular injury.

Bo Kyoung Kim, Tatiana Goncharov, Sébastien A Archaimbault, Filip Roudnicky, Joshua D Webster, Peter D Westenskow, Domagoj Vucic.

Receptor-interacting protein 1 (RIP1, RIPK1) is a critical mediator of multiple signaling pathways that promote inflammatory responses and cell death. The kinase activity of RIP1 contributes to the pathogenesis of a number of inflammatory and neurodegenerative diseases. However, the role of RIP1 in retinopathies remains unclear. This study demonstrates that RIP1 inhibition protects retinal ganglion cells (RGCs) in preclinical glaucoma models. Genetic inactivation of RIP1 improves RGC survival and preserves retinal function in the preclinical glaucoma models of optic nerve crush (ONC) and ischemia-reperfusion injury (IRI). In addition, the involvement of necroptosis in ONC and IRI glaucoma models was examined by utilizing RIP1 kinase-dead (RIP1-KD), RIP3 knockout (RIP3-KO), and MLKL knockout (MLKL-KO) mice. The number of RGCs, retinal thickness, and visual acuity were rescued in RIP1-kinase-dead (RIP1-KD) mice in both models, while wild-type (WT) mice experienced significant retinal thinning, RGC loss, and vision impairment. RIP3-KO and MLKL-KO mice showed moderate protective effects in the IRI model and limited in the ONC model. Furthermore, we confirmed that a glaucoma causative mutation in optineurin, OPTN-E50K, sensitizes cells to RIP1-mediated inflammatory cell death. RIP1 inhibition reduces RGC death and axonal degeneration following IRI in mice expressing OPTN-WT and OPTN-E50K variant mice. We demonstrate that RIP1 inactivation suppressed microglial infiltration in the RGC layer following glaucomatous damage. Finally, this study highlights that human glaucomatous retinas exhibit elevated levels of TNF and RIP3 mRNA and microglia infiltration, thus demonstrating the role of neuroinflammation in glaucoma pathogenesis. Altogether, these data indicate that RIP1 plays an important role in modulating neuroinflammation and that inhibiting RIP1 activity may provide a neuroprotective therapy for glaucoma.

DOI: https://doi.org/10.1038/s41418-024-01390-7
Theranostics. 2024 ;14(16): 6319-6336

PET imaging of microglia in Alzheimer's disease using copper-64 labeled TREM2 antibodies.

Monireh Shojaei, Rebecca Schaefer, Kai Schlepckow, Lea H Kunze, Felix L Struebing, Bettina Brunner, Michael Willem, Laura M Bartos, Astrid Feiten, Giovanna Palumbo, Thomas Arzberger, Peter Bartenstein, Gian Carlo Parico, Dan Xia, Kathryn M Monroe, Christian Haass, Matthias Brendel, Simon Lindner.

  Triggering receptor expressed on myeloid cells 2 (TREM2) plays an essential role in microglia activation and is being investigated as a potential therapeutic target for modulation of microglia in several neurological diseases. In this study, we present the development and preclinical evaluation of 64Cu-labeled antibody-based PET radiotracers as tools for non-invasive assessment of TREM2 expression. Furthermore, we tested the potential of an antibody transport vehicle (ATV) that binds human transferrin receptor to facilitate transcytosis of TREM2 antibody-based radiotracers to the CNS and improve target engagement. Methods: A TREM2 antibody with an engineered transport vehicle (ATV:4D9) and without (4D9) were covalently modified with pNCS-benzyl-NODAGA and labeled with copper-64. Potency, stability, and specificity were assessed in vitro followed by in vivo PET imaging at the early 2 h, intermediate 20 h, and late imaging time points 40 h post-injection using a human transferrin receptor (hTfR) expressing model for amyloidogenesis (5xFAD;TfRmu/hu) or wild-type mice (WT;TfRmu/hu), and hTfR negative controls. Organs of interest were isolated to determine biodistribution by ex vivo autoradiography. Cell sorting after in vivo tracer injection was used to demonstrate cellular specificity for microglia and to validate TREM2 PET results in an independent mouse model for amyloidogenesis (AppSAA;TfRmu/hu). For translation to human imaging, a human TREM2 antibody (14D3) was radiolabeled and used for in vitro autoradiography on human brain sections. Results: The 64Cu-labeled antibodies were obtained in high radiochemical purity (RCP), radiochemical yield (RCY), and specific activity. Antibody modification did not impact TREM2 binding. ATV:4D9 binding proved to be specific, and the tracer stability was maintained over 48 h. The uptake of [64Cu]Cu-NODAGA-ATV:4D9 in the brains of hTfR expressing mice was up to 4.6-fold higher than [64Cu]Cu-NODAGA-4D9 in mice without hTfR. TREM2 PET revealed elevated uptake in the cortex of 5xFAD mice compared to wild-type, which was validated by autoradiography. PET-to-biodistribution correlation revealed that elevated radiotracer uptake in brains of 5xFAD;TfRmu/hu mice was driven by microglia-rich cortical and hippocampal brain regions. Radiolabeled ATV:4D9 was selectively enriched in microglia and cellular uptake explained PET signal enhancement in AppSAA;TfRmu/hu mice. Human autoradiography showed elevated TREM2 tracer binding in the cortex of patients with Alzheimer's disease. Conclusion: [64Cu]Cu-NODAGA-ATV:4D9 has potential for non-invasive assessment of TREM2 as a surrogate marker for microglia activation in vivo. ATV engineering for hTfR binding and transcytosis overcomes the blood-brain barrier restriction for antibody-based PET radiotracers. TREM2 PET might be a versatile tool for many applications beyond Alzheimer's disease, such as glioma and chronic inflammatory diseases.

Keywords:  ATV:4D9; PET; TREM2; copper-64; microglia

DOI:  https://doi.org/10.7150/thno.97149
Neural Regen Res. 2024 Oct 22.

Microglia overexpressing brain-derived neurotrophic factor promote vascular repair and functional recovery in mice after spinal cord injury.

Fanzhuo Zeng, Yuxin Li, Xiaoyu Li, Xinyang Gu, Yue Cao, Shuai Cheng, He Tian, Rongcheng Mei, Xifan Mei.

ABSTRACT: Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited. Microglia is the resident immune cells of the central nervous system, play a critical role in spinal cord injury. Previous studies have shown that microglia can promote neuronal survival by phagocytosing dead cells and debris and by releasing neuroprotective and anti-inflammatory factors. However, excessive activation of microglia can lead to persistent inflammation and contribute to the formation of glial scars, which hinder axonal regeneration. Despite this, the precise role and mechanisms of microglia during the acute phase of spinal cord injury remain controversial and poorly understood. To elucidate the role of microglia in spinal cord injury, we employed the colony-stimulating factor 1 receptor inhibitor PLX5622 to deplete microglia. We observed that sustained depletion of microglia resulted in an expansion of the lesion area, downregulation of brain-derived neurotrophic factor, and impaired functional recovery after spinal cord injury. Next, we generated a transgenic mouse line with conditional overexpression of brain-derived neurotrophic factor specifically in microglia. We found that brain-derived neurotrophic factor overexpression in microglia increased angiogenesis and blood flow following spinal cord injury and facilitated the recovery of hindlimb motor function. Additionally, brain-derived neurotrophic factor overexpression in microglia reduced inflammation and neuronal apoptosis during the acute phase of spinal cord injury. Furthermore, through using specific transgenic mouse lines, TMEM119, and the colony-stimulating factor 1 receptor inhibitor PLX73086, we demonstrated that the neuroprotective effects were predominantly due to brain-derived neurotrophic factor overexpression in microglia rather than macrophages. In conclusion, our findings suggest the critical role of microglia in the formation of protective glial scars. Depleting microglia is detrimental to recovery of spinal cord injury, whereas targeting brain-derived neurotrophic factor overexpression in microglia represents a promising and novel therapeutic strategy to enhance motor function recovery in patients with spinal cord injury.

DOI: https://doi.org/10.4103/NRR.NRR-D-24-00381
J Neuroinflammation. 2024 Oct 21. 21(1): 270

Microglia ameliorate delirium-like phenotypes in a murine model of acute ventilator-induced lung injury.

Landon Scott, Kevin D Winzey, Debbie Moreira, Catherine Bresee, Jean-Philippe Vit, Warren G Tourtellotte, S Ananth Karumanchi, Shouri Lahiri.

   BACKGROUND: Delirium affects 50-85% of patients on mechanical ventilation and is associated with increased mortality, prolonged hospitalization, and a three-fold higher risk of dementia. Microglia, the resident immune cells of the brain, exhibit both neuroprotective and neurotoxic functions; however, their effects in mechanical ventilation-induced acute lung injury (VILI) are unknown. We hypothesize that in a model of short-term VILI, microglia play a neuroprotective role to ameliorate delirium-like phenotypes.
METHODS: Microglia depletion (n = 18) was accomplished using an orally administered colony stimulating factor 1 receptor inhibitor, while controls received a vehicle diet (n = 18). We then compared extent of neuronal injury in the frontal cortex and hippocampus using cleaved caspase-3 (CC3) and multiple delirium-like behaviors in microglia depleted and non-microglia depleted male mice (C57BL/6 J aged 4-9 months) following VILI. Delirium-like behaviors were evaluated using the Open Field, Elevated Plus Maze, and Y-maze assays. We subsequently evaluated whether repopulation of microglia (n = 14 repopulation, 14 vehicle) restored the phenotypes.
RESULTS: Frontal/hippocampal neuronal CC3 levels were significantly higher in microglia depleted VILI mice compared to vehicle-treated VILI controls (p < 0.01, p < 0.01, respectively). These structural changes were accompanied by worse delirium-like behaviors in microglia depleted VILI mice compared to vehicle controls. Specifically, microglia depleted VILI mice demonstrated: (1) significantly increased time in the periphery of the Open Field (p = 0.01), (2) significantly increased coefficient of variation (p = 0.02), (3) trend towards reduced time in the open arms of the Elevated Plus Maze (p = 0.09), and (4) significantly decreased spontaneous alternations on Y-maze (p < 0.01). There was a significant inverse correlation between frontal CC3 and percent spontaneous alternations (R2 = 0.51, p < 0.01). Microglia repopulation showed a near-complete return to vehicle levels of delirium like-behaviors.
CONCLUSIONS: This study demonstrates that microglia depletion exacerbates structural and functional delirium-like phenotypes after VILI, while subsequent repopulation of microglia restores these phenotypes. These findings suggest a neuroprotective role for microglia in ameliorating neuronal and functional delirium-like phenotypes and call for consideration of interventions that leverage endogenous microglia physiology to mitigate delirium.

Keywords:  Delirium; Mechanical ventilation; Microglia; Ventilator-induced lung injury

DOI:  https://doi.org/10.1186/s12974-024-03260-y
Invest Ophthalmol Vis Sci. 2024 Oct 01. 65(12): 38

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

Chunlian Ou, Yiwei Lin, Jing Wen, Hongyang Zhang, Ying Xu, Naiyuan Zhang, Qiong Liu, Yingzi Wu, Jing Xu, Jing Wu.

Purpose: Retinal ischemia-reperfusion (RIR) injury is implicated in various retinal diseases, leading to retinal ganglion cells (RGCs) degeneration. Microglial senescence exacerbates inflammation, contributing to neurodegeneration. This study aimed to investigate the potential therapeutic role of Roflumilast (Roflu) in ameliorating microglial senescence and neuroinflammation following RIR injury.
Methods: C57BL/6J mice underwent RIR surgery, and Roflu treatment was administered intraperitoneally. BV2 microglial cells were subjected to oxygen-glucose deprivation and reoxygenation (OGD/R) to simulate ischemic conditions in vitro. SA-β-gal staining was used to detect cellular senescence. Quantitative PCR and ELISA were used to examine the levels of senescence-associated secretory phenotype (SASP) factors. Hematoxylin and eosin (H&E) staining was performed on retinal sections to assess retinal morphology and thickness. Surviving RGCs were labeled and quantified in retinal whole-mounts using immunofluorescence (IF). Furthermore, Western blot and IF staining were used to quantify the proteins associated with the cell cycle and NLRP3 inflammasomes.
Results: Roflu treatment reduced microglial senescence, ROS production, and secretion of pro-inflammatory cytokines in OGD/R-exposed BV2 cells. It also restored cell proliferation capacity and reversed OGD/R-induced cell cycle arrest. In vivo, Roflu alleviated retinal senescence, preserved retinal thickness, and protected against RGCs death in the RIR mouse model. Mechanistically, Roflu inhibited the NLRP3 inflammasome activation and suppressed DNA damage signaling pathway in microglia.
Conclusions: Roflu exerts neuroprotective effects by mitigating microglial senescence and inflammation via inhibition of the NLRP3 inflammasome in RIR injury. These findings suggest that Roflu may serve as a promising therapeutic strategy for retinal diseases associated with ischemic injury by targeting microglial senescence.

DOI: https://doi.org/10.1167/iovs.65.12.38
Commun Biol. 2024 Oct 22. 7(1): 1373

Loss of CLN3 in microglia leads to impaired lipid metabolism and myelin turnover.

Seda Yasa, Elisabeth S Butz, Alessio Colombo, Uma Chandrachud, Luca Montore, Sarah Tschirner, Matthias Prestel, Steven D Sheridan, Stephan A Müller, Janos Groh, Stefan F Lichtenthaler, Sabina Tahirovic, Susan L Cotman.

Loss-of-function mutations in CLN3 cause juvenile Batten disease, featuring neurodegeneration and early-stage neuroinflammation. How loss of CLN3 function leads to early neuroinflammation is not yet understood. Here, we have comprehensively studied microglia from Cln3∆ex7/8 mice, a genetically accurate disease model. Loss of CLN3 function in microglia leads to lysosomal storage material accumulation and abnormal morphology of subcellular organelles. Moreover, pathological proteomic signatures are indicative of defects in lysosomal function and abnormal lipid metabolism. Consistent with these findings, CLN3-deficient microglia are unable to efficiently turnover myelin and metabolize the associated lipids, showing defects in lipid droplet formation and cholesterol accumulation. Accordingly, we also observe impaired myelin integrity in aged Cln3∆ex7/8 mouse brain. Autophagy inducers and cholesterol-lowering drugs correct the observed microglial phenotypes. Taken together, these data implicate a cell-autonomous defect in CLN3-deficient microglia that impacts their ability to support neuronal cell health, suggesting microglial targeted therapies should be considered for CLN3 disease.

DOI: https://doi.org/10.1038/s42003-024-07057-w
Glia. 2024 Oct 22.

Three-dimensional view of microglia-amyloid plaque interactions.

Maria Gotkiewicz, Janne Capra, Pasi O Miettinen, Teemu Natunen, Heikki Tanila.

  Recent gene expression studies have revealed about 10 different states of microglia, some of which are characteristic for Alzheimer-like amyloid plaque pathology. However, it is not presently known how these translate into morphological features that would reflect microglia interaction with amyloid plaques. With optimized conditions for confocal microscopy in amyloid plaque forming APP/PS1 transgenic mice we reveal new details of how microglia processes interact with amyloid plaques. The microglia contacts differed drastically between purely diffuse plaque and those with a fibrillar core. We identified microglia that extend their enlarged processes through the diffuse shell of the amyloid plaques and cover the fibrillar plaque core with snowplow-like expanded end-feet. These end-feet were filled with the lysosomal marker CD68, while both non-fibrillar and fibrillar amyloid was found in perinuclear vesicles of some "snowplower" microglia. In the organized dense-core plaques, we consistently saw a layer of Apolipoprotein E (ApoE) between the fibrillar core and the microglial end-feet. ApoE covered also loose fibrillar amyloid and diffuse amyloid plaques that were about 10 μm or larger in diameter. These findings are compatible with both amyloid plaque phagocytosis and compaction by microglia. Further, they support a chemotactic role of ApoE for microglia contacts with amyloid plaques.

Keywords:  3D rendering; ApoE; confocal imaging; dense‐core plaque; transgenic mice

DOI:  https://doi.org/10.1002/glia.24628
J Neuroinflammation. 2024 Oct 23. 21(1): 273

The deficient CLEC5A ameliorates the behavioral and pathological deficits via the microglial Aβ clearance in Alzheimer's disease mouse model.

Yu-Yi Lin, Wen-Han Chang, Shie-Liang Hsieh, Irene Han-Juo Cheng.

   BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease that causes cognitive dysfunction in older adults. One of the AD pathological factors, β-Amyloid (Aβ), triggers inflammatory responses and phagocytosis of microglia. C-type lectin domain family 5 member A (CLEC5A) induces over-reactive inflammatory responses in several virus infections. Yet, the role of CLEC5A in AD progression remains unknown. This study aimed to elucidate the contribution of CLEC5A to Aβ-induced microglial activation and behavioral deficits.
METHODS: The AD mouse model was crossed with Clec5a knockout mice for subsequent behavioral and pathological tests. The memory deficit was revealed by the Morris water maze, while the nociception abnormalities were examined by the von Frey filament and hotplate test. The Aβ deposition and microglia recruitment were identified by ELISA and immunohistochemistry. The inflammatory signals were identified by ELISA and western blotting. In the Clec5a knockdown microglial cell model and Clec5a knockout primary microglia, the microglial phagocytosis was revealed using the fluorescent-labeled Aβ.
RESULTS: The AD mice with Clec5a knockout improved Aβ-induced memory deficit and abnormal nociception. These mice have reduced Aβ deposition and increased microglia coverage surrounding the amyloid plaque, suggesting the involvement of CLEC5A in AD progression and Aβ clearance. Moreover, the phagocytosis was also increased in the Aβ-stressed Clec5a knockdown microglial cell lines and Clec5a knockout primary microglia.
CONCLUSION: The Clec5a knockout ameliorates AD-like deficits by modulating microglial Aβ clearance. This study implies that targeting microglial Clec5a could offer a promising approach to mitigate AD progression.

Keywords:  Alzheimer’s disease; C-type lectin domain family 5 member A (CLEC5A); Microglia; β-amyloid (Aβ)

DOI:  https://doi.org/10.1186/s12974-024-03253-x
Cell Biochem Biophys. 2024 Oct 25.

METTL14 Promotes Ischemic Stroke-induced Brain Injury by Stabilizing HDAC3 Expression in an m6A-IGF2BP3 Mechanism.

Xuelin Liang, Songhe Yin, Canfang Hu, Dingzhong Tang, Guojun Luo, Zhen Liu.

  N6-methyladenosine (m6A) modification is the most abundant post-transcriptional modification of mRNAs and has been identified to play critical roles in ischemic stroke (IS). Herein, this study aimed to investigate the function and mechanism of Methyltransferase-like 14 (METTL14) methylase in cerebral IS. Murine BV-2 microglial cell OGD/R models and rat middle cerebral artery occlusion (MCAO) models were established to mimic IS-induced neuronal damage in vitro and brain injury in vivo. Levels of METTL14, Histone Deacetylase 3 (HDAC3) and cGAS-STING axis-related proteins were detected using qRT-PCR or western blotting. Cell proliferation and inflammation were assessed by CCK-8 assay, EdU assay and ELISA. Flow cytometry detected microglia polarization. Cell pyroptosis was analyzed by detecting related-protein markers by western blotting. The m6A modification was determined by methylated RNA immunoprecipitation assay. Brain injury was analyzed by evaluating infarct volume and neurologic score. METTL14 levels were higher in OGD/R-induced microglial cells, primary microglia and infarct brain tissues of rat MCAO models. Functionally, METTL14 silencing reversed OGD/R-induced proliferation inhibition, inflammation and pyroptosis in microglial cells and primary microglia in vitro, and ameliorated cerebral ischemic injury in rat MCAO models. Mechanistically, METTL14 induced HDAC3 m6A modification in an IGF2BP3-dependent manner, and could activate cGAS-STING pathway through HDAC3. Moreover, HDAC3 overexpression reversed the neuroprotective effects of METTL14 silencing. METTL14 silencing reversed ischemic stroke-induced brain injury by inducing HDAC3 m6A modification in an IGF2BP3-dependent mechanism, recommending a novel insight for ameliorating cerebral ischemic stroke.

Keywords:  Inflammation; Microglia; NLRP3 inflammasome; Pyroptosis; m6A

DOI:  https://doi.org/10.1007/s12013-024-01596-z
CNS Neurosci Ther. 2024 Oct;30(10): e70088

Microglial Melatonin Receptor 1 Degrades Pathological Alpha-Synuclein Through Activating LC3-Associated Phagocytosis In Vitro.

Xiao-Yu Yao, Bing-Er Cao, Jun-Yi Liu, Qian-Kun Lv, Jia-Rui Zhang, Xiao-Yu Cheng, Cheng-Jie Mao, Quan-Hong Ma, Fen Wang, Chun-Feng Liu.

   AIMS: Parkinson's disease (PD) is characterized by the formation of Lewy bodies (LBs), primarily constituted of α-synuclein (α-Syn). Microglial cells exhibit specific reactivity toward misfolded proteins such as α-Syn. However, the exact clearance mechanism and related molecular targets remain elusive.
METHODS: BV2 cells, primary microglia from wild-type and MT1 knockout mice, and primary cortical neurons were utilized as experimental models. The study investigated relevant mechanisms by modulating microglial MT1 expression through small RNA interference (RNAi) and lentiviral overexpression techniques. Furthermore, pathological aggregation of α-Syn was induced using pre-formed fibrils (PFF) α-Syn. Co-immunoprecipitation, immunofluorescence, Western blot (WB), and quantitative real-time PCR were used to elucidate the mechanisms of molecular regulation.
RESULTS: In this study, we elucidated the regulatory role of the melatonin receptor 1 (MT1) in the microglial phagocytic process. Following MT1 knockout, the ability of microglial cells to engulf latex beads and zymosan particles decreased, subsequently affecting the phagocytic degradation of fibrillar α-Syn by microglial cells. Furthermore, the loss of MT1 receptors in microglial cells exacerbates the aggregation of α-Syn in neurons induced by pre-formed fibrils (PFF) α-Syn. Mechanistically, MT1 influences the phagocytic function of microglial cells by regulating the Rubicon-dependent LC3-associated phagocytosis (LAP) pathway.
CONCLUSION: Taken together, the results suggest the neuroprotective function of microglial cells in clearing α-Syn through MT1-mediated LAP, highlighting the potential key role of MT1 in pathogenic mechanisms associated with α-Syn.

Keywords:  LC3‐associated phagocytosis; Parkinson's disease; melatonin receptor 1; microglia; α‐synuclein

DOI:  https://doi.org/10.1111/cns.70088
Adv Neurobiol. 2024 ;42 263-283

Age at Injury as a Modifier of Preclinical TBI Behavioral, Neuropathological, and Inflammatory Outcomes.

Wai Hang Cheng, Mehwish Anwer, Jianjia Fan, Honor Cheung, Kevin Zhang, Cheryl Wellington.

  Traumatic brain injury (TBI) is a leading cause of injury-related death and disability. In high-income countries, TBI is most prevalent among the older population (≥65 years), commonly caused by falls. Though age at injury is associated with increased risk of mortality and poor outcome, the underlying mechanisms are unclear. Studies in animal models may yield insights into the intersection of TBI with age. Here we review recent studies in animal models where TBI induced in aged animals is associated with exacerbated behavioral deficits (e.g., mortality, thigmotaxis, and cognitive deficits), neuropathology (microgliosis and astrogliosis), neuroinflammation (e.g., cytokines and iNOS), microglial alterations (e.g., more cellular vesicles and adopting a damage-associated microglia gene signature), and cell signaling and pathway changes (e.g., complement, phagocytosis, autophagy, trophic factor signaling). As relatively few preclinical studies focus on aged animals, more research is needed to fully understand the pathophysiology of TBI in the aged population. Particularly, we recommend that (1) more aged animals should be used, (2) closed-head TBI models should be considered, and (3) animal models of comorbidity or polytrauma should be considered.

Keywords:  Age at injury; Age-dependent; Ageing; Behavior; Neuroinflammation; Traumatic brain injury

DOI:  https://doi.org/10.1007/978-3-031-69832-3_13
Glia. 2024 Oct 22.

The antipsychotic chlorpromazine reduces neuroinflammation by inhibiting microglial voltage-gated potassium channels.

Hee-Yoon Lee, Young Lee, Chaelin Chung, Seo-In Park, Hyo Jung Shin, Eun-Hye Joe, Sung Joong Lee, Dong Woon Kim, Su-Hyun Jo, Se-Young Choi.

  Neuroinflammation, the result of microglial activation, is associated with the pathogenesis of a wide range of psychiatric and neurological disorders. Recently, chlorpromazine (CPZ), a dopaminergic D2 receptor antagonist and schizophrenia therapy, was proposed to exert antiinflammatory effects in the central nervous system. Here, we report that the expression of Kv1.3 channel, which is abundant in T cells, is upregulated in microglia upon infection, and that CPZ specifically inhibits these channels to reduce neuroinflammation. In the mouse medial prefrontal cortex, we show that CPZ lessens Kv1.3 channel activity and reduces proinflammatory cytokine production. In mice treated with LPS, we found that CPZ was capable of alleviating both neuroinflammation and depression-like behavior. Our findings suggest that CPZ acts as a microglial Kv1.3 channel inhibitor and neuroinflammation modulator, thereby exerting therapeutic effects in neuroinflammatory psychiatric/neurological disorders.

Keywords:  Kv1.3 channel; chlorpromazine; microglia; neuroinflammation; psychiatric disease

DOI:  https://doi.org/10.1002/glia.24629
Nat Commun. 2024 Oct 24. 15(1): 9095

Interaction between subventricular zone microglia and neural stem cells impacts the neurogenic response in a mouse model of cortical ischemic stroke.

Suvra Nath, Jose C Martínez Santamaría, Yu-Hsuan Chu, James S Choi, Pasquale Conforti, Jia-Di Lin, Roman Sankowski, Lukas Amann, Christos Galanis, Kexin Wu, Sachin S Deshpande, Andreas Vlachos, Marco Prinz, Jae K Lee, Christian Schachtrup.

After a stroke, the neurogenic response from the subventricular zone (SVZ) to repair the brain is limited. Microglia, as an integral part of the distinctive SVZ microenvironment, control neural stem / precursor cell (NSPC) behavior. Here, we show that discrete stroke-associated SVZ microglial clusters negatively impact the innate neurogenic response, and we propose a repository of relevant microglia-NSPC ligand-receptor pairs. After photothrombosis, a mouse model of ischemic stroke, the altered SVZ niche environment leads to immediate activation of microglia in the niche and an abnormal neurogenic response, with cell-cycle arrest of neural stem cells and neuroblast cell death. Pharmacological restoration of the niche environment increases the SVZ-derived neurogenic repair and microglial depletion increases the formation and survival of newborn neuroblasts in the SVZ. Therefore, we propose that altered cross-communication between microglial subclusters and NSPCs regulates the extent of the innate neurogenic repair response in the SVZ after stroke.

DOI: https://doi.org/10.1038/s41467-024-53217-1
Front Aging Neurosci. 2024 ;16 1411104

Emerging role of microglia in inter-cellular transmission of α-synuclein in Parkinson's disease.

Xiangbo Zhang, Haiyang Yu, Juan Feng.

  Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, significantly prejudicing the health and quality of life of elderly patients. The main pathological characteristics of PD are the loss of dopaminergic neurons in the substantia nigra (SN) as well as abnormal aggregation of α-synuclein (α-syn) monomers and oligomers, which results in formation of Lewy bodies (LBs). Intercellular transmission of α-syn is crucial for PD progression. Microglia play diverse roles in physiological and pathological conditions, exhibiting neuroprotective or neurotoxic effects; moreover, they may directly facilitate α-syn propagation. Various forms of extracellular α-syn can be taken up by microglia through multiple mechanisms, degraded or processed into more pathogenic forms, and eventually released into extracellular fluid or adjacent cells. This review discusses current literature regarding the molecular mechanisms underlying the uptake, degradation, and release of α-syn by microglia.

Keywords:  Parkinson’s disease; microglia; neurodegeneration; propagation; α-synuclein

DOI:  https://doi.org/10.3389/fnagi.2024.1411104
Arthritis Res Ther. 2024 Oct 23. 26(1): 183

WIF-1 contributes to lupus-induced neuropsychological deficits via the CRYAB/STAT4-SHH axis.

Liping Tan, Yu Fan, Xinyi Xu, Tianshu Zhang, Xiangyu Cao, Chenghao Zhang, Jun Liang, Yayi Hou, Huan Dou.

   BACKGROUND: Neuropsychiatric systemic lupus erythematosus (NPSLE) often manifests as cognitive deterioration, with activated microglia and blood-brain barrier (BBB) disruption implicated in these neurological complications. Wnt-inhibitory factor-1 (WIF-1), a secreted protein, has been detected in the cerebrospinal fluid (CSF) of NPSLE patients. However, the contribution of WIF-1 in contributing to lupus cognitive impairment remains poorly understood.
METHODS: Using MRL/MpJ-Faslpr (MRL/lpr) lupus-prone mice and TLR7 agonist imiquimod (IMQ)-induced lupus mice, recombinant WIF-1 protein (rWIF-1) and adeno-associated virus (AAV) encoding sh-WIF-1 were administered via intracerebroventricular injection. Behavioral tests, histopathological examinations, flow cytometry, and molecular biology techniques were employed to investigate the underlying mechanisms.
RESULTS: Microinjection of rWIF-1 exacerbated cognitive deficits and mood abnormalities, increased BBB leakage and neuronal degeneration, and caused aberrant activation of microglia and synaptic pruning in the hippocampus. Conversely, lupus mice injected with AAV-shWIF-1 exhibited significant remission. In vitro, rWIF-1 induced overactivation of microglia with an increased CD86+ pro-inflammatory subpopulation, upregulated phagocytic activity, and excessive synaptic engulfment, contributing to increased BBB permeability. Furthermore, WIF-1 exerted its biological effects through the CRYAB/STAT4 pathway, transcriptionally decreasing SHH production. We also identified that symmetric dimethylarginine (SDMA) could alleviate rWIF-1-induced microglial activation and BBB damage, thereby restoring SHH levels.
CONCLUSIONS: In conclusion, WIF-1 exacerbates lupus-induced cognitive dysfunction in mice by triggering aberrant microglial activation and BBB disruption through the CRYAB/STAT4-SHH axis, highlighting the potential therapeutic effects of SDMA for the treatment of NPSLE.

Keywords:  Blood-brain barrier; Microglia; Neuropsychiatric systemic lupus erythematosus; WIF-1

DOI:  https://doi.org/10.1186/s13075-024-03420-8
Exp Neurol. 2024 Oct 18. pii: S0014-4886(24)00346-7. [Epub ahead of print] 115020

SARS-CoV-2 spike S1 protein induces microglial NLRP3-dependent neuroinflammation and cognitive impairment in mice.

Qiuhong Jiang, Ge Li, Huacheng Wang, Weineng Chen, Fengyin Liang, Haifan Kong, Tara S R Chen, Lishan Lin, Hua Hong, Zhong Pei.

  Cognitive impairment is often found at the acute stages and sequelae of coronavirus disease 2019 (COVID-19), and the underlying mechanisms remain unclear. The S1 protein from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be a cause of cognitive impairment associated with COVID-19. The nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome and neuroinflammation play important roles in Alzheimer's disease (AD) with cognitive impairment. However, their roles remain unknown in COVID-19 with cognitive impairment. We stimulated BV2 cells with S1 protein in vitro and injected the hippocampi of wild-type (WT) mice, NLRP3 knockout (KO), and microglia NLRP3 KO mice in vivo with S1 protein to induce cognitive impairment. We assessed exploratory behavior as associative memory using novel object recognition and Morris water maze tests. Neuroinflammation was analyzed using immunofluorescence and western blotting to detect inflammatory markers. Co-localized NLRP3 and S1 proteins were investigated using confocal microscopy. We found that S1 protein injection led to cognitive impairment, neuronal loss, and neuroinflammation by activating NLRP3 inflammation, and this was reduced by global NLRP3 KO and microglia NLRP3 KO. Furthermore, TAK 242, a specific inhibitor of Toll-like receptor-4, resulted in a significant reduction in NLRP3 and pro-IL-1β in BV2 cells with S1 protein stimulation. These results reveal a distinct mechanism through which the SARS-CoV-2 spike S1 protein promotes NLRP3 inflammasome activation and induces excessive inflammatory responses.

Keywords:  Cognitive impairment; Coronavirus disease 2019; NLRP3 inflammasome; Neuroinflammation; SARS-CoV-2 spike s1 protein

DOI:  https://doi.org/10.1016/j.expneurol.2024.115020
Neurobiol Dis. 2024 Oct 21. pii: S0969-9961(24)00312-7. [Epub ahead of print]202 106711

Senolytic therapy preserves blood-brain barrier integrity and promotes microglia homeostasis in a tauopathy model.

Minmin Yao, Zhiliang Wei, Jonathan Scharff Nielsen, Yuxiao Ouyang, Aaron Kakazu, Haitong Wang, Lida Du, Ruoxuan Li, Tiffany Chu, Susanna Scafidi, Hanzhang Lu, Manisha Aggarwal, Wenzhen Duan.

  Cellular senescence, characterized by expressing the cell cycle inhibitory proteins, is evident in driving age-related diseases. Senescent cells play a crucial role in the initiation and progression of tau-mediated pathology, suggesting that targeting cell senescence offers a therapeutic potential for treating tauopathy associated diseases. This study focuses on identifying non-invasive biomarkers and validating their responses to a well-characterized senolytic therapy combining dasatinib and quercetin (D + Q), in a widely used tauopathy mouse model, PS19. We employed human-translatable MRI measures, including water extraction with phase-contrast arterial spin tagging (WEPCAST) MRI, T2 relaxation under spin tagging (TRUST), longitudinally assessed brain physiology and high-resolution structural MRI evaluated the brain regional volumes in PS19 mice. Our data reveal increased BBB permeability, decreased oxygen extraction fraction, and brain atrophy in 9-month-old PS19 mice compared to their littermate controls. (D + Q) treatment effectively preserves BBB integrity, rescues cerebral oxygen hypometabolism, attenuates brain atrophy, and alleviates tau hyperphosphorylation in PS19 mice. Mechanistically, D + Q treatment induces a shift of microglia from a disease-associated to a homeostatic state, reducing a senescence-like microglial phenotype marked by increased p16/Ink4a. D + Q-treated PS19 mice exhibit enhanced cue-associated cognitive performance in the tracing fear conditioning test compared to the vehicle-treated littermates, implying improved cognitive function by D + Q treatment. Our results pave the way for application of senolytic treatment as well as these noninvasive MRI biomarkers in clinical trials in tauopathy associated neurological disorders.

Keywords:  Blood-brain barrier; MRI; Microglia; Senescence; Senolytic therapy; Tau

DOI:  https://doi.org/10.1016/j.nbd.2024.106711