# Development of Novel Therapeutics for the Treatment of Alzheimer's Disease

> **NIH NIH U54** · MONTANA STATE UNIVERSITY - BOZEMAN · 2020 · $337,458

## Abstract

Alzheimer’s disease (AD) is the most common cause of dementia and is the sixth leading cause of death in
the United States. More than 5.8 million people live with AD today, and it is projected that by the year 2050,
nearly 14 million people will be affected by this devastating disease. For American Indian and Alaska Native
(AI/AN) communities, the effects of AD and related dementias (ADRD) will likely have an even greater impact
because of the higher prevalence of risk factors associated with AD/ADRD. Indeed, the number of AI/ANs living
with dementia is projected to grow over five-fold by 2060. This increase in the number of older AI/AN adults
living with dementia will have a significant and detrimental impact on the vitality of whole communities. In order
to address this epidemic, new therapeutics are needed that target specific pathways associated with AD/ADRD
pathogenesis. For example, a significant amount of research suggests that neuroinflammation plays an active
role in AD pathogenesis and that microglial cells bind to soluble amyloid β (Aβ) oligomers and Aβ fibrils via cell-
surface formyl peptide receptor 2 (FPR2), resulting in an inflammatory response. Thus, we hypothesize that
specific therapeutics that target and disrupt microglial cell activation pathways and inflammatory
polarization could interrupt the harmful inflammatory events contributing to AD pathogenesis and favor
a microglial M2 polarization that resolves inflammation.
 We propose to address this hypothesis by characterizing the human microglial inflammatory responses
induced by soluble and aggregated Aβ, including intracellular Ca2+ flux, reactive oxygen species (ROS)
production, cytokine/chemokine production, and nuclear factor κB (NF-κB) activation. We will also characterize
microglial inflammatory phenotype switching (M1/M2) and gene expression (RNA-Seq) in response to Aβ
activation. We will then evaluate effects of novel small molecule FPR2 antagonists on human microglial cell
inflammatory responses to determine which compounds are effective inhibitors of inflammation and can enhance
microglial M2 polarization. We have discovered a large number of FPR2 ligands over the years, including some
specific for FPR2 and some with mixed receptor specificity for FPR1/FPR2, which can be biased towards FPR2.
This library of FPR2 ligands will be useful for initial screening but will be followed by structure-activity relationship
(SAR) analysis, molecular modeling, and acquisition/synthesis of new analogs.
 The accomplishment of these preclinical studies will lead to the development of a new class of
prospective compounds that could be developed for the treatment of AD/ADRD, which could
significantly benefit the AI/AN Communities. This is clearly an innovative approach to treating a prevalent
disease where there are few effective drugs. The proposal will also address significant knowledge gaps relevant
to the mechanisms of microglial inflammation induced by amyloid peptides. Further ...

## Key facts

- **NIH application ID:** 10121243
- **Project number:** 3U54GM115371-05S1
- **Recipient organization:** MONTANA STATE UNIVERSITY - BOZEMAN
- **Principal Investigator:** MARK T QUINN
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $337,458
- **Award type:** 3
- **Project period:** 2016-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10121243

## Citation

> US National Institutes of Health, RePORTER application 10121243, Development of Novel Therapeutics for the Treatment of Alzheimer's Disease (3U54GM115371-05S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10121243. Licensed CC0.

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