# Discovery of functionally selective Alzheimer's disease therapeutics

> **NIH NIH R01** · UNIVERSITY OF NORTH TEXAS HLTH SCI CTR · 2020 · $749,313

## Abstract

Abstract
The prevalence of Alzheimer's disease (AD) and the associated financial and caregiver burden is projected to escalate
dramatically unless disease-modifying treatments are discovered. Our research is focused on addressing this urgent unmet
medical and societal need through the discovery and development of pharmacotherapies capable of averting or delaying
the progression of AD. Brain inflammation initiated by chronic oxidative-nitrosative stress is a proven component of the
pathogenic cascade leading to mild cognitive impairment (MCI) and AD. When surplus inflammatory nitric oxide and
superoxide molecules combine they form the brain-impairing reactive species peroxynitrite. This perpetuates
inflammation resulting in the progressive neurodegeneration observed in AD. Our innovative approach consists of
managing two processes associated with inflammatory disease progression. The first involves interrupting the cycle of
peroxynitrite generation by suppressing unsafe elevations in nitric oxide triggered by oxidative stress, and the second
involves enhancing resilience to and recovery from inflammatory insults by facilitating the secretion of brain-derived
neurotrophic factor (BDNF). A single stress-activated chaperone protein is mechanistically capable of both mediating
BDNF secretion and regulating nitric oxide levels under proinflammatory conditions. Preliminary studies have identified
chemotype starting points for further CNS drug development which have the desired dual functional selectivity profile for
this target receptor. Our plan is to optimize the CNS drug-like properties of these functionally selective chemotypes with
the goal of developing medicines that can significantly modify the course of MCI/AD.

## Key facts

- **NIH application ID:** 9931103
- **Project number:** 5R01AG055072-04
- **Recipient organization:** UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
- **Principal Investigator:** ROBERT R LUEDTKE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $749,313
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9931103

## Citation

> US National Institutes of Health, RePORTER application 9931103, Discovery of functionally selective Alzheimer's disease therapeutics (5R01AG055072-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9931103. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*