A novel approach for targeting neuroinflammation in brain aging and Alzheimer's disease

Colorado State University, Fort Collins CO

Investigators

Abstract

PROJECT SUMMARY Aging increases the risk for Alzheimer’s disease (AD), but as described in NOT-AG-21-039, the underlying mechanisms are poorly understood. In this R21 project we propose to test the efficacy of a novel therapeutic targeting neuroinflammation for protecting against brain aging and AD-related pathology, and to evaluate the role of the key neuroinflammation mediators NF-κB and NLRP3 in this context. Our rationale is based on pilot studies we performed using NF-κB/NLRP3-targeted Nanoligomers, a novel class of clinically translatable small molecules that specifically downregulate gene targets of interest. Our pilot data show that Nanoligomers targeting NF-κB and NLRP3 have the potential to reduce neuroinflammation, enhance memory (one key domain of cognitive function that declines with aging and predicts AD risk) and favorably modulate the brain transcriptome in both aging wild-type mice and a transgenic, AD-relevant mouse model. Based on these observations, we propose a series of comprehensive pre-clinical studies in which we will test the efficacy of NF-κB/NLRP3-Nanoligomers for reducing neuroinflammation and protecting different domains of cognitive function with aging vs. AD-related pathology by administering NF-κB/NLRP3-Nanoligomers to: 1) old wild-type mice; and 2) transgenic mouse models of both amyloid beta (Aβ) and tau pathology (the main pathological features of AD). In all models, we will conduct a battery of cognitive-behavioral tests to comprehensively evaluate the functional effects of NF-κB/NLRP3-Nanoligomer treatment, and we will perform brain region- specific transcriptomics (RNA-seq) and analyses of numerous neuroinflammation and pathological markers. We also will perform 3) a series of complementary bioinformatics analyses using existing human datasets to determine if there is greater evidence of NF-κB/NLRP3-associated neuroinflammation with aging vs. pathology in the human brain. Together, the results of these experiments will allow us to determine the ideal application of NF-κB/NLRP3-Nanoligomers (i.e., prevention during aging vs. treatment of pathology), and to establish evidence for the role of NF-κB/NLRP3-associated neuroinflammation in these specific contexts (an important question in research on brain aging and AD). Our aims are specifically designed to enable a future R01 project, as they will provide a basis for larger studies aimed at understanding age- vs. pathology-related neuroinflammation and insight into how and when to administer Nanoligomers in pilot clinical trials.