Nanopolymer Targeting NF-κB and NLRP3 Reduces Neuroinflammation and Enhances Cognitive Function in Aging and Tauopathy

Research Background

Aging is a major risk factor for cognitive decline and most neurodegenerative diseases, such as Alzheimer’s disease (AD). These cognitive declines are closely related to the pathological aggregation of Tau protein, a hallmark of AD that increases with age. A key macroscopic mechanism is neuroinflammation, characterized by the activation of innate immune signaling, glial cell activation, decline in neuronal health, and the release of neurotoxic pro-inflammatory cytokines. Therefore, identifying strategies to reduce neuroinflammation is of significant importance in the context of aging and Tau proteinopathies.

The NF-κB and NLRP3 signaling axis are major drivers of aging and Tau-related neuroinflammation and play a central role in promoting adverse processes in brain aging and AD. However, current therapies targeting NF-κB or NLRP3 may have undesirable systemic effects, and most have not yet been translated clinically. In this study, we tested a novel nucleic acid therapy (nanopolymer) cocktail specifically targeting NF-κB and NLRP3 in the brain to reduce neuroinflammation and enhance cognitive function in aged (19-month-old) wild-type mice and RTG4510 mice with Tau pathology.

Research Source

This study, conducted by Wahl et al., was published in the Journal of Neuroinflammation (2024) 21:182. The authors include researchers from the Department of Health and Exercise Science, Department of Environmental and Radiological Health Sciences, Brain Research Center, Columbine Health Systems Center for Healthy Aging, Sachi Bio, and Colorado Technology Center at Colorado State University. The article is available under open-access licensing, allowing use, sharing, adaptation, distribution, and reproduction in any medium or format, provided proper credit is given to the original authors and source, a link to the Creative Commons license is provided, and any changes made are indicated.

Research Process and Results

The study involved the following steps:

a) Four weeks of NF-κB/NLRP3-targeted nanopolymer treatment on 19-month-old mice. Results showed significant reductions in neuroinflammatory cytokines in the brain and improved cognitive behavioral functions.

b) The nanopolymer treatment was associated with reduced glial cell activation and pathology, favorable changes in transcriptomic features (reduced glial cell-associated inflammation, increased neuronal health), and positive systemic effects.

The study results provide a foundation for future translational research targeting NF-κB and NLRP3 in the brain, potentially using nanopolymers to inhibit neuroinflammation and improve cognitive function in aging and neurodegenerative diseases.

Significance and Value of the Research

The scientific value of this study lies in providing a new strategy for reducing neuroinflammation and improving cognitive function associated with aging and neurodegenerative diseases. Targeting NF-κB and NLRP3 with nanopolymers shows potential therapeutic applications in different animal models and provides a theoretical basis for similar studies in larger animal models and/or clinical trials in the future.

Research Highlights

An important finding of this study is that nanopolymers targeting NF-κB and NLRP3 can improve cognitive function in aging and Tauopathy mouse models. The innovation of this new research approach or workflow lies in its targeted therapeutic strategy and its potential therapeutic value for the brain.

Other Noteworthy Content

The study also found that NF-κB/NLRP3-targeted nanopolymer treatment is beneficial not only for the brain but also has positive effects on liver and peripheral health, further expanding the potential application scope of this therapeutic strategy.