# Analysis of Nrf1 pathway in Alzheimer's Disease

> **NIH NIH R03** · VIRGINIA COMMONWEALTH UNIVERSITY · 2022 · $310,500

## Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is
characterized by cognitive decline and memory loss. One of the defining pathological
hallmarks of AD at the molecular level is the presence of neurofibrillary tangles
composed of aggregates of hyperphosphorylated tau in the neurons. These aggregates
impose a severe burden on the neuronal protein quality control pathways resulting in
severe proteotoxic stress in these cells. Sustained proteotoxic stress typically results in
neuronal cell death culminating in brain atrophy, a prominent pathological feature of AD.
Our previous work has firmly established the transcription factor Nrf1 as a central player
in responding to cellular proteotoxic stress. Nrf1, by its ability to induce de novo
synthesis of proteasome subunit genes in response to proteasome inhibition, promotes
the recovery of proteasome activity, thus mitigating proteotoxic stress and enhancing
cellular survival. However, whether or not the Nrf1 pathway is active in AD neurons
experiencing proteotoxic stress is currently unclear. Using cell line-based models of AD,
here we propose to interrogate the functional status of the Nrf1 pathway. Also, using a
loss-of-function genetic screen, we propose to uncover kinase(s) that could act as
negative regulator(s) of the Nrf1 pathway. If successful, our studies could help elucidate
the role of the Nrf1 pathway in AD-afflicted neuronal cells and set the stage for future
studies aimed at developing novel therapeutics to boost neuronal protein degradation
pathways to enable tau clearance and thereby mitigate proteotoxic stress.

## Key facts

- **NIH application ID:** 10288256
- **Project number:** 1R03AG073884-01
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Senthil Kumar Radhakrishnan
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $310,500
- **Award type:** 1
- **Project period:** 2022-05-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10288256

## Citation

> US National Institutes of Health, RePORTER application 10288256, Analysis of Nrf1 pathway in Alzheimer's Disease (1R03AG073884-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10288256. Licensed CC0.

---

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