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

Award Number: R21AG085456
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $115,500 )
2025	2025	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Aging Research	000	2	6/3/2025	NON-COMPETING CONTINUATION	$115,500
														Subtotal = $115,500

Issue Date FY: 2024 ( Subtotal = $281,962 )
2024	2024	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Aging Research	000	1	9/26/2024	NEW	$281,962
														Subtotal = $281,962

Grand Total All Awards = $397,462

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

Award Number: R21AG085456

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/30/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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