Nanoligomers targeting NF-κB and NLRP3 reduce neuroinflammation and improve cognitive function with aging and tauopathy

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: July 27, 2024

Abstract Neuroinflammation contributes to impaired cognitive function in brain aging and neurodegenerative disorders like Alzheimer’s disease, which is characterized by the aggregation of pathological tau. One major driver both age- tau-associated neuroinflammation NF-κB NLRP3 signaling axis. However, current treatments targeting or may have adverse/systemic effects, most not been clinically translatable. In this study, we tested efficacy a novel, nucleic acid therapeutic (Nanoligomer) cocktail specifically for reducing improving old (aged 19 months) wildtype mice, rTg4510 tau pathology mice 2 months). We found that 4 weeks NF-κB/NLRP3-targeting Nanoligomer treatment strongly reduced neuro-inflammatory cytokine profiles improved cognitive-behavioral mice. These effects Nanoligomers were also associated with glial cell activation pathology, favorable changes transcriptome signatures glia-associated inflammation (reduced) neuronal health (increased), positive systemic effects. Collectively, our results provide basis future translational studies brain, perhaps using Nanoligomers, inhibit improve neurodegeneration.

Language: Английский

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Neuroprotective effects of magnesium: implications for neuroinflammation and cognitive decline

Frontiers in Endocrinology, Journal Year: 2024, Volume and Issue: 15

Published: Sept. 25, 2024

Neurodegenerative diseases, which are characterized by progressive neuronal loss and cognitive decline, a significant concern for the aging population. Neuroinflammation, shared characteristic of these is implicated in their pathogenesis. This article briefly summarizes role magnesium, an essential mineral involved numerous enzymatic reactions critical bioactivity, context neuroinflammation decline. The potential neuroprotective effects including mechanisms neuroprotection magnesium through maintaining ion homeostasis, reducing inflammation, preventing excitotoxicity, also described. Additionally, we discuss impact inadequate on its as therapeutic agent attenuating decline to improve neurodegenerative conditions.

Language: Английский

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Large- and Small-Animal Studies of Safety, Pharmacokinetics, and Biodistribution of Inflammasome-Targeting Nanoligomer in the Brain and Other Target Organs

ACS Pharmacology & Translational Science, Journal Year: 2024, Volume and Issue: 7(11), P. 3439 - 3451

Published: March 21, 2024

Immune malfunction or misrecognition of healthy cells and tissue, termed autoimmune disease, is implicated in more than 80 disease conditions multiple other secondary pathologies. While pan-immunosuppressive therapies like steroids can offer limited relief for systemic inflammation some organs, many patients never achieve remission, such drugs do not cross the blood-brain barrier, making them ineffective tackling neuroinflammation. Especially brain, unintended activation microglia astrocytes hypothesized to be directly indirectly responsible sclerosis, amyotrophic lateral Parkinson's Alzheimer's disease. Recent studies have also shown that targeting inflammasomes specific immune targets beneficial these diseases. Furthermore, our previous NF-κB NLRP3 through brain penetrant Nanoligomer cocktail SB_NI_112 (abbreviated as NI112) therapeutic several neurodegenerative Here, we show safety-toxicity studies, followed by pharmacokinetics biodistribution small- (mice) large-animal (dog) this inflammasome-targeting NI112. We conducted using four different routes administration: intravenous, subcutaneous, intraperitoneal, intranasal, identified drug concentration over time inductively coupled plasma mass spectrometry blood serum, (including regions), target organs liver, kidney, colon. Our results indicate has a strong safety profile shows high (

Language: Английский

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Targeted-Neuroinflammation Mitigation Using Inflammasome-Inhibiting Nanoligomers is Therapeutic in an Experimental Autoimmune Encephalomyelitis Mouse Model

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: 15(7), P. 1596 - 1608

Published: March 25, 2024

Multiple sclerosis (MS) is a debilitating autoimmune disease that impacts millions of patients worldwide, disproportionately impacting women (4:1), and often presenting at highly productive stages life. This affects the spinal cord brain characterized by severe neuroinflammation, demyelination, subsequent neuronal damage, resulting in symptoms like loss mobility. While untargeted pan-immunosuppressive therapies have proven to be disease-modifying manage (or prolong time between) many patients, significant fraction are unable achieve remission. Recent work has suggested targeted neuroinflammation mitigation through selective inflammasome inhibition can offer relief while preserving key components immune function. Here, we show screening potential therapeutic targets using inflammasome-inhibiting Nanoligomers (NF-κB1, TNFR1, TNF-α, IL-6) meet or far-exceed commercially available small-molecule counterparts ruxolitinib, MCC950, deucravacitinib. Using human organoid model, top Nanoligomer combinations (NF-κB1 + TNFR1: NI111, NF-κB1 NLRP3: NI112) were shown significantly reduce without any observable negative impact on Further testing these an aggressive experimental encephalomyelitis (EAE) mouse model for MS intraperitoneal (IP) injections showed NLRP3 targeting combination NI112 rescues mice mobility disability, minimal inflammation histology, no cell infiltration similar par with received EAE (negative control). Mice receiving NI111 TNFR1) also reduced compared saline (sham)-treated par/similar other small molecule treatments, although it was higher than leading worsening clinical outcomes. Furthermore, treatment oral formulation lower doses reduction severity, albeit variance owing administration formulation/fill-and-finish variability. Overall, results point further development inflammasome-targeting Nanoliogmers as effective multiple neurodegenerative diseases potentially benefit several suffering from such MS.

Language: Английский

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Nanoligomers targeting NF-κB and NLRP3 reduce neuroinflammation and improve cognitive function with aging and tauopathy

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 7, 2024

ABSTRACT Neuroinflammation contributes to impaired cognitive function in brain aging and neurodegenerative disorders like Alzheimer’s disease, which is characterized by the aggregation of pathological tau. One major driver both age- tau-associated neuroinflammation NF-κB NLRP3 signaling axis. However, current treatments targeting or may have adverse/systemic effects, most not been clinically translatable. In this study, we tested efficacy a novel, nucleic acid therapeutic (Nanoligomer) cocktail specifically for reducing improving old (aged 19 months) wildtype mice, rTg4510 tau pathology mice 2 months). We found that 4 weeks NF-κB/NLRP3-targeting Nanoligomer treatment strongly reduced neuro-inflammatory cytokine profiles improved cognitive-behavioral mice. These effects Nanoligomers were also associated with glial cell activation pathology, favorable changes transcriptome signatures glia-associated inflammation (reduced) neuronal health (increased), positive systemic effects. Collectively, our results provide basis future translational studies brain, perhaps using Nanoligomers, inhibit improve neurodegeneration.

Language: Английский

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Reactive Oxygen Species as a Common Pathological Link Between Alcohol Use Disorder and Alzheimer’s Disease with Therapeutic Implications

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(7), P. 3272 - 3272

Published: April 1, 2025

Chronic alcohol consumption leads to excessive production of reactive oxygen species (ROS), driving oxidative stress that contributes both use disorder (AUD) and Alzheimer's disease (AD). This review explores how ROS-mediated mitochondrial dysfunction neuroinflammation serve as shared pathological mechanisms linking these conditions. We highlight the role alcohol-induced damage in exacerbating neurodegeneration compare ROS-related pathways AUD AD. Finally, we discuss emerging therapeutic strategies, including antioxidants inflammasome inhibitors, target mitigate neurodegeneration. Understanding overlapping may provide new insights for preventing treating ROS-driven neurodegenerative disorders.

Language: Английский

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Targeting NLRP3 Inflammasomes: A Trojan Horse Strategy for Intervention in Neurological Disorders

Molecular Neurobiology, Journal Year: 2024, Volume and Issue: unknown

Published: July 23, 2024

Language: Английский

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NF-κB/NLRP3 Translational Inhibition by Nanoligomer Therapy Mitigates Ethanol and Advanced Age-Related Neuroinflammation

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 28, 2024

Binge alcohol use is increasing among aged adults (>65 years). Alcohol-related toxicity in associated with neurodegeneration, yet the molecular underpinnings of age-related sensitivity to are not well described. Studies utilizing rodent models neurodegenerative disease reveal heightened activation Nuclear factor kappa-light-chain-enhancer activated B cells (NF-κB) and Nod like receptor 3 (NLRP3) mediate microglia neuronal injury. Our group, others, have implicated hippocampal-resident as key producers inflammatory mediators, link between inflammation neurodegeneration has been established binge ethanol exposure advanced age. Here, we report increased proportion NLRP3

Language: Английский

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Inflammasome-Inhibiting Nanoligomers Are Neuroprotective against Space-Induced Pathology in Healthy and Diseased Three-Dimensional Human Motor and Prefrontal Cortex Brain Organoids

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: 15(16), P. 3009 - 3021

Published: July 31, 2024

The microgravity and space environment has been linked to deficits in neuromuscular cognitive capabilities, hypothesized occur due accelerated aging neurodegeneration space. While the specific mechanisms are still being investigated, spaceflight-associated neuropathology is an important health risk astronauts tourists actively investigated for development of appropriate countermeasures. However, such space-induced offers opportunity screening therapeutic targets lead molecules treating neurodegenerative diseases. Here, we show a proof-of-concept high-throughput target (on Earth), validation, mitigation microgravity-induced using our Nanoligomer platform, onboard 43-day SpaceX CRS-29 mission International Space Station. First, comparing 3D healthy diseased prefrontal cortex (PFC, cognition) motor neuron (MN, function) organoids, assessed pathology biomarkers relevant Alzheimer's disease (AD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS). Both PFC MN organoids showed significantly enhanced space, as measured through biomarkers, when compared their respective Earth controls. Second, tested top two molecules, NI112 that targeted NF-κB NI113 IL-6. We observed these Nanoligomers mitigate AD, FTD, ALS like amyloid beta-42 (Aβ42), phosphorylated tau (pTau), Kallikrein (KLK-6), Tar DNA-binding protein 43 (TDP-43), others. Moreover, treatment brain did not appear cause any observable toxicity or safety issues organoid tissue, suggesting good tolerability at physiologically doses. Together, results significant potential both translation neuroprotective countermeasures safer travel demonstrate usefulness rapid, clinical translation. assert use drug may ultimately benefit millions patients suffering from debilitating diseases on Earth.

Language: Английский

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Microbiome- and Host Inflammasome-Targeting Inhibitor Nanoligomers Are Therapeutic in the Murine Colitis Model

ACS Pharmacology & Translational Science, Journal Year: 2024, Volume and Issue: 7(9), P. 2677 - 2693

Published: Aug. 30, 2024

Autoimmune and autoinflammatory diseases account for more than 80 chronic conditions affecting 24 million people in the US. Among these diseases, noninfectious inflammation of gastrointestinal (GI) tract causes inflammatory bowel (IBDs), primarily Crohn's ulcerative colitis (UC). IBD is a complex disease, one hypothesis that are either caused or worsened by compounds produced bacteria gut. While traditional approaches have focused on pan immunosuppressive techniques (e.g., steroids), low remission rates, prolonged illnesses, an increased frequency surgical procedures prompted search targeted precision therapeutic approaches. disease resulting from both genetic environmental factors, but several recent studies highlighted potential pivotal contribution gut microbiota dysbiosis. Gut known to modulate immune status producing metabolites encoded biosynthetic gene clusters (BGCs) bacterial genome. Here, we show high-throughput screening 90 genes 41 anaerobes, through downselection using available bioinformatics tools, manipulation genetically intractable organisms Nanoligomer platform, identification synthesis top microbiome targets as BGC cocktail (SB_BGC_CK1, abbreviated CK1) feasible approach. Further, used host-directed target identify NF-κB NLRP3 SB_NI_112 (or NI112 short) inflammasome inhibitor. We two microbe- host-targeted cocktails acute dextran sulfate sodium (DSS) mouse TNF

Language: Английский

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