# Pro-Electrophilic Drugs PEDs for Alzheimer's Disease

> **NIH NIH R56** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $885,611

## Abstract

We propose a novel target and new drug to treat Alzheimer’s disease (AD) via the Nrf2 transcriptional
pathway. Our drug candidates for this target are currently at the stage of active hit-to-lead optimization, as
described below. As background, AD is a condition with loss of synapses and neurons in the brain,
characterized by the presence of amyloid beta (Aβ) plaques and tau tangles, which cause damage to
synapses and neurons at least partially via oxidative stress. Our prior studies have indicated that carnosic acid
(CA), a component compound in the herb Rosemary, can protect neurons and synapses from damage caused
by oxidative stress by activating the Nrf2 transcriptional pathway. Our Preliminary Data show that CA treatment
ameliorates various behavioral and histological deficits in AD transgenic mutant mice, while showing no
significant side effects. Activation of the Keap1/Nrf2 (kelch-like ECH-associated protein 1/nuclear factor
erythroid 2-related factor 2) pathway upregulates transcription of phase II antioxidant and anti-inflammatory
proteins. We and others have shown that this can be a valuable therapeutic strategy in several
neurodegenerative diseases. Here, we further test this approach in mouse models of AD using carnosic acid
(CA), which we have shown in our publications to activate the Keap1/Nrf2 pathway. CA is known to be
clinically tolerated because of its presence in herbs like Rosemary. Conversely, in humans with AD, a
decreased expression pattern of Nrf2 in hippocampal neurons and astrocytes, as well as a significant decrease
in nuclear Nrf2 levels in frontal cortex, have been reported. The Keap1/Nrf2 pathway can be activated by an
electrophilic compound when it reacts with a specific thiol on Keap1, releasing Nrf2 in the cytoplasm to enter
the nucleus where it binds to the antioxidant responsive element (ARE) on the promoters of phase II genes. An
important issue clinically with regard to electrophilic drugs (such as dimethyl fumarate, curcumin, and
Bardoloxone) is that they not only react with Keap1 to activate Nrf2, but they also non-specifically react with
other thiol groups, which may explain both their actions and side effects. Our alternative, innovative strategy to
avoid such side effects is to use pro-electrophilic compounds that are activated by the very oxidation in
redox-stressed cells that is injurious. The compound CA represents a starting point for such a pro-electrophilic
drug (PED). Accordingly, our Specific Aims/Goals are –
Aim/Goal 1. To screen for and characterize the neuroprotective effects of PEDs that activate the
Nrf2/ARE transcriptional pathway in an in vitro model of oligomeric Aß-induced oxidative damage and
neuroinflammation using hiPSC-derived cortical neurons and cerebral organoids.
 Aim/Goal 2. To determine the lead PED by assessing neuroprotective effects by neurobehavior and
histology in vivo in AD transgenic mouse models (hAPP-J20 and 3x Tg mice) and optimize formulation of the
lead. Toxicity te...

## Key facts

- **NIH application ID:** 10230417
- **Project number:** 1R56AG065372-01
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** STUART A LIPTON
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $885,611
- **Award type:** 1
- **Project period:** 2020-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10230417

## Citation

> US National Institutes of Health, RePORTER application 10230417, Pro-Electrophilic Drugs PEDs for Alzheimer's Disease (1R56AG065372-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10230417. Licensed CC0.

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