Increased inflammasome protein expression identified in microglia from postmortem brains with schizophrenia

Journal of Neuropathology & Experimental Neurology, Journal Year: 2024, Volume and Issue: 83(11), P. 951 - 966

Published: June 21, 2024

Abstract Schizophrenia (SCZ) is a complex psychiatric disorder that involves an inflammatory response thought to be characterized by microglial activation. The inflammasome may play critical roles in the pathomechanism of neuroinflammation but how this relates SCZ remains unclear. In study, we performed immunohistochemical (IHC) analysis compare expression proteins brain tissue from donors with (n = 16) and non-psychiatric (NP; n 13) isolated superior frontal cortex (SFC), temporal cortex, anterior cingulate regions. To assess changes cell populations express key proteins, IHC analyses apoptosis-associated speck-like protein containing CARD (ASC), nod-like receptor 3 (NLRP3), interleukin (IL)-18 determine if these are expressed microglia, astrocytes, oligodendrocytes, or neurons. Inflammasome were mainly microglia NP brains. Increased numbers present SFC brains exhibited higher ASC, NLRP3, IL-18 compared NPs. These findings suggest increased signaling contribute pathology underlying SCZ.

Language: Английский

---

Sex Differences in the Inflammatory Profile in the Brain of Young and Aged Mice

Cells, Journal Year: 2023, Volume and Issue: 12(10), P. 1372 - 1372

Published: May 12, 2023

Neurodegenerative diseases are a leading cause of death worldwide with no cures identified. Thus, there is critical need for preventative measures and treatments as the number patients expected to increase. Many neurodegenerative have sex-biased prevalence, indicating examine sex differences when investigating prevention treatment strategies. Inflammation key contributor many promising target since inflammation increases age, which known inflammaging. Here, we analyzed protein expression levels cytokines, chemokines, inflammasome signaling proteins in cortex young aged male female mice. Our results show an increase caspase-1, interleukin (IL)-1β, apoptosis-associated speck-like containing caspase recruitment domain (ASC), ASC specks females compared males. Additionally, was IL-1α, VEGF-A, CCL3, CXCL1, CCL4, CCL17, CCL22 aging IL-8, IL-17a, IL-7, LT-α, IL-12/IL-23p40, CCL13, IL-10 were increased males but not age. These indicate that cortical inflammaging provide potential targets attenuate prevent development disease.

Language: Английский

---

Beneficial Effects of Human Schwann Cell-Derived Exosomes in Mitigating Secondary Damage After Penetrating Ballistic-Like Brain Injury

Journal of Neurotrauma, Journal Year: 2024, Volume and Issue: 41(21-22), P. 2395 - 2412

Published: March 6, 2024

There is a growing body of evidence that the delivery cell-derived exosomes normally involved in intracellular communication can reduce secondary injury mechanisms after brain and spinal cord improve outcomes. Exosomes are nanometer-sized vesicles released by Schwann cells may have neuroprotective effects reducing posttraumatic inflammatory processes as well promoting tissue healing functional recovery. The purpose this study was to evaluate beneficial human Schwann-cell (hSC-Exos) severe model penetrating ballistic-like (PBBI) rats investigate on multiple Human cell processing protocols followed Current Good Manufacturing Practices (cGMP) with exosome extraction purification steps approved FDA for an expanded access single ALS patient IND. Anesthetized male Sprague-Dawley (280-350g) underwent PBBI surgery or sham procedures starting 30 min received either dose hSC-Exos PBS through jugular vein. At 48hrs PBBI, flow cytometry analysis cortical revealed administration reduced number activated microglia levels caspase-1, marker inflammasome activation. Neuropathological at 21 days showed treatment significantly overall contusion volume decreased frequency Iba-1 positive amoeboid immunocytochemical analysis. This systemic TBI reduces histopathological damage. represents clinically relevant cell-based therapy limit detrimental neurotrauma other progressive neurological injuries impacting pathophysiological events

Language: Английский

---

Extracellular vesicles mediate inflammasome signaling in the brain and heart of Alzheimer’s disease mice

Frontiers in Molecular Neuroscience, Journal Year: 2024, Volume and Issue: 17

Published: April 10, 2024

Introduction Alzheimer’s disease (AD) is an inflammatory neurodegenerative characterized by memory loss and cognitive impairment that worsens over time. AD associated with many comorbidities, including cardiovascular are poorer outcomes. Comorbidities, especially heart stroke, play a significant role in the demise of patients. Thus, it important to understand how comorbidities linked AD. We have previously shown extracellular vesicle (EV)-mediated inflammasome signaling plays pathogenesis brain injury acute lung after traumatic injury. Methods analyzed cortical, hippocampal, ventricular, atrial protein lysates from APP/PS1 mice their respective controls for activation. Additionally, we serum-derived EV size, concentration, content proteins as well marker CD63. Finally, performed conditioned media experiments patients healthy age-matched delivered cells culture assess EV-induced inflammation. Results show increase Pyrin, NLRP1, caspase-1, ASC cortex whereas caspase-8, ASC, IL-1β were significantly elevated ventricles when compared controls. did not find differences size or concentration between groups, but there was caspase-1 In addition, resulted activation, increases TNF-α IL-2. Conclusion These results indicate EV-mediated may development diseases

Language: Английский

---

Human Schwann cell exosome treatment attenuates secondary injury mechanisms, histopathological consequences, and behavioral deficits after traumatic brain injury

Neurotherapeutics, Journal Year: 2025, Volume and Issue: unknown, P. e00555 - e00555

Published: Feb. 1, 2025

Language: Английский

---

Gasdermin-D Genetic Knockout Reduces Inflammasome-Induced Disruption of the Gut-Brain Axis After Traumatic Brain Injury

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(8), P. 3512 - 3512

Published: April 9, 2025

Traumatic brain injury (TBI) pathology is significantly mediated by an inflammatory response involving inflammasome activation, resulting in the release of interleukin (IL)-1β and pyroptotic cell death through gasdermin-D (GSDMD) cleavage. Inflammasome components are transported extracellular vesicles (EVs) to mediate systemic inflammation peripheral organs, including gut. The purpose this study was determine protective effect GSDMD knockout (KO) on TBI-induced EV signaling, gut function. GSDMD-KO C57BL6 (WT) mice were subjected controlled cortical impact model TBI. Cytokine expression assessed with electrochemiluminescent immunoassay immunoblotting cerebral cortex EVs examined for pathology-associated markers using flow cytometry, permeability determined. attenuated IL-1β IL-6 reduced IL-18 3 days post-injury. had decreased neuronal- gut-derived compared WT post-TBI. also different surface marker after These data demonstrate that ablation improves post-TBI pathology, suggesting may serve as a potential therapeutic target improvement TBI-associated pathologies.

Language: Английский

---

IC100, a humanized therapeutic monoclonal anti-ASC antibody alleviates oxygen-induced retinopathy in mice

Angiogenesis, Journal Year: 2024, Volume and Issue: 27(3), P. 423 - 440

Published: May 6, 2024

Abstract Background Retinopathy of prematurity (ROP), which often presents with bronchopulmonary dysplasia (BPD), is among the most common morbidities affecting extremely premature infants and a leading cause severe vision impairment in children worldwide. Activations inflammasome cascade microglia have been implicated playing role development both ROP BPD. Apoptosis-associated speck-like protein containing caspase recruitment domain (ASC) pivotal assembly. Utilizing mouse models oxygen-induced retinopathy (OIR) BPD, this study was designed to test hypothesis that hyperoxia induces ASC speck formation, leads microglial activation retinopathy, inhibition formation by humanized monoclonal antibody, IC100, directed against ASC, will ameliorate abnormal retinal vascular formation. Methods We first tested retina ASC-citrine reporter mice expressing fusion C-terminal citrine (fluorescent GFP isoform) using BPD model causes lung eye injury exposing newborn room air (RA) or 85% O 2 from postnatal day (P) 1 P14. The retinas were dissected on P14 flat mounts used detect endothelium AF-594-conjugated isolectin B4 (IB4) citrine-tagged specks. To assess effects IC100 an OIR model, wildtype (C57BL/6 J) exposed RA P1 P6, then 75% P7 P11, P12 P18. At randomized following groups: placebo PBS (RA-PBS), (O -PBS), + intravitreal injection -IC100-IVT), intraperitoneal -IC100-IP). Retinal vascularization evaluated mount staining IB4. Microglial detected immunofluorescence for allograft inflammatory factor (AIF-1) CD206. structure analyzed H&E-stained sections, function pattern electroretinography (PERG). RNA-sequencing (RNA-seq) performed determine transcriptional treatment OIR. Results specks significantly increased exposure colocalized vasculature models, associated activation. Treatment IC100-IVT IC100-IP reduced vaso-obliteration neovascularization. also activation, restored structure, improved function. RNA-seq showed corrected induction genes angiogenesis, leukocyte migration, VEGF signaling caused . suppression cell junction assembly, neuron projection, recognition Conclusion These data demonstrate crucial pathogenesis efficacy therapeutic anti-ASC antibody treating mice. Thus, may potentially be considered diseases oxygen stresses such as ROP.

Language: Английский

---

Inflammasome links traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer’s disease

Neural Regeneration Research, Journal Year: 2024, Volume and Issue: 20(6), P. 1644 - 1664

Published: July 10, 2024

Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer’s disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela of neuroinflammation includes the pathologic hyperphosphorylation tau protein, an endogenous microtubule-associated protein protects integrity neuronal cytoskeletons. Tau results in misfolding subsequent accumulation tangles forming neurotoxic aggregates. These misfolded proteins characteristic can lead to downstream neuroinflammatory processes, including assembly activation inflammasome complex. Inflammasomes refer a family multimeric units that, upon activation, release cascade signaling molecules resulting caspase-induced cell death inflammation mediated by interleukin-1β cytokine. specific inflammasome, NOD-like receptor 3, has been proposed be key regulator phosphorylation where it shown prolonged 3 acts as causal factor pathological spreading. This review begins describing epidemiology pathophysiology disease. Next, we highlight overriding theme discuss role formation deposits how such tauopathic entities spread throughout brain. We then propose novel framework linking inflammasome-dependent pathologies exist along temporal continuum. Finally, potential therapeutic targets may intercept this pathway ultimately minimize long-term decline.

Language: Английский

---

Nanocarrier-mediated siRNA delivery: a new approach for the treatment of traumatic brain injury–related Alzheimer's disease

Neural Regeneration Research, Journal Year: 2024, Volume and Issue: 20(9), P. 2538 - 2555

Published: Sept. 24, 2024

Traumatic brain injury and Alzheimer’s disease share pathological similarities, including neuronal loss, amyloid-β deposition, tau hyperphosphorylation, blood–brain barrier dysfunction, neuroinflammation, cognitive deficits. Furthermore, traumatic can exacerbate disease-like pathologies, potentially leading to the development of disease. Nanocarriers offer a potential solution by facilitating delivery small interfering RNAs across for targeted silencing key genes implicated in Unlike traditional approaches neuroregeneration, this is molecular-targeted strategy, thus avoiding non-specific drug actions. This review focuses on use nanocarrier systems efficient precise siRNAs, discussing advantages, challenges, future directions. In principle, siRNAs have target all non-targetable proteins, holding significant promise treating various diseases. Among therapeutic currently available neurological diseases, siRNA gene precisely “turn off” expression any at genetic level, radically inhibiting progression; however, challenge lies delivering barrier. Nanoparticles received increasing attention as an innovative tool treatment They are considered strategy with advantages being able cross barrier, delivery, enhanced stability, multifunctional therapy. The nanoparticles deliver specific modified injured gradually recognized feasible effective approach. Although still preclinical exploration stage, it expected achieve clinical translation future, creating new field molecular therapy precision medicine associated injury.

Language: Английский

---

Immunohistochemical Detection of Axonal Injury in Chimpanzee (Pan troglodytes) with Traumatic and Fatal Brain Injury

Macedonian Veterinary Review, Journal Year: 2024, Volume and Issue: 47(2), P. 179 - 189

Published: June 18, 2024

Abstract Estimating the time of death after traumatic brain injury (TBI) in wildlife is a significant challenge forensic veterinary medicine. The understanding histopathological changes and predicting survival can prompt critical emergency measures health management strategies for animals managed care. Glial fibrillary acidic protein (GFAP) well-established astrocytic biomarker diagnosing, monitoring, TBI outcomes. Moreover, buildup Beta-Amyloid Precursor Protein (βAPP) resulting from axonal damage an energetic process intricately connected to period following injury. To date, no study has explored accumulation GFAP βAPP chimpanzees. In human studies, earliest reported detecting postmortem using approximately 30 minutes. This aimed investigate whether staining be used detect within minutes Cerebral cerebellar tissues chimpanzee control samples were screened immunopositivity neurons immunohistochemistry immunofluorescence. results suggested that neuronal was likely artifact, as negative controls also showed staining. However, it not easy assume absence post-traumatic GFAP. Conversely, assay indicated detected 22 death, marking fastest recorded date aiding diagnosing severe with short times. conclusion, we demonstrated captivated caused by sudden concussion

Language: Английский

---