Risen, S. J. | bioRxiv Science

bioRxiv2024

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

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

physiology↗

bioRxiv2022

Targeting neuroinflammatory pathways using Nanoligomer is neuroprotective in prion disease

Neuroinflammation plays a crucial role in the development of neurodegenerative protein misfolding disorders. This category of progressive diseases includes, but is not limited to, Alzheimers disease, Parkinsons disease, and prion diseases. Shared pathogenesis involves the accumulation of misfolded proteins, chronic neuroinflammation, and synaptic dysfunction, ultimately leading to irreversible neuronal loss, measurable cognitive deficits, and death. Presently, there are little to no effective treatments to halt the advancement of neurodegenerative diseases. We hypothesized directly targeting neuroinflammation by downregulating the transcription factor, NF-{kappa}B and the inflammasome protein, NLRP3, with the brain-penetrant, non-toxic, SB_NI_112, would be neuroprotective. To achieve this, we used a cocktail of RNA targeting therapeutics (SB_NI_112) shown to be brain-penetrant, non-toxic, and targeting both NF-|B and NLRP3. We utilized a mouse-adapted prion strain as a model for neurodegenerative diseases to assess aggregation of misfolded proteins, glial inflammation, neuronal loss, cognitive deficits, and lifespan. Prion-diseased mice were treated either intraperitoneally or intranasally with SB_NI_112. Behavioral and cognitive deficits were significantly protected by this combination of NF-{kappa}B and NLRP3 down-regulators. Treatment reduced glial inflammation, protected against neuronal loss, prevented spongiotic change, rescued cognitive deficits, and significantly lengthened lifespan of prion-diseased mice. We have identified a non-toxic, systemic pharmacologic that down-regulates NF-|B and NLRP3, prevents neuronal death and slows the progression of neurodegenerative disease. Though mouse models do not always predict human patient success, and the study was limited due to sample size and number of dosing methods utilized, these findings serve as a proof of principle for continued translation of the therapeutic SB_NI_112 for prion disease and other neurodegenerative diseases. Based on success in a murine prion model, we will be continual testing SB_NI_112 in a variety of neurodegenerative disease models, including Alzheimers Disease and Parkinsons Disease.

neuroscience↗