# Exploring Alzheimer Therapeutics

> **NIH VA I01** · EDITH NOURSE  ROGERS MEMORIAL VETERANS HOSPITAL · 2022 · —

## Abstract

Abstract
 This project will advance the re-positioning of a novel therapeutic agent, fasudil, for the treatment of
Alzheimer’s disease (AD). Currently there is a huge unmet need for safe and effective disease modifying
therapies to treat and prevent AD. This study will generate preclinical pharmacological outcomes to prepare for
the USA FDA application for AD clinical trials and extend our studies of the mechanism of action (MOA) of
fasudil in cells and the 3X-Tg AD mouse model of disease. Both PIs have extensive experience in the
molecular biology and pathology of AD, the biological activity of fasudil and Wnt signaling, and in preclinical
drug development; we are ideally positioned to evaluate the efficacy and the MOA of fasudil and test our
hypothesis that fasudil down-regulates non-canonical (Planar Cell Polarity (PCP)) Wnt signaling and the
downstream effects of Dickkopf-1 (Dkk1), leading to reduced Tau phosphorylation. Specifically, we will
achieve three Aims. Aim 1. To determine PK of fasudil in WT and 3X-Tg AD mice after acute and chronic
oral dosing (PO). We will determine the brain/plasma ratio of novel fasudil metabolites after IV delivery of
fasudil to mice, and then determine the time of maximum concentration observed (Tmax), half-life (t1/2), peak
plasma concentration (Cmax), area under the curve (AUC), and bioavailability of fasudil after PO dosing. We will
determine steady-state fasudil exposure in plasma and brain in a multiple-PO dosing paradigm, and finally
confirm PK profile in 3X-Tg AD transgenic mice. We will specifically identify the most permeable fasudil
metabolites and establish the active pharmaceutical ingredient for monitoring PK profiling. Data from acute
dosing of fasudil will be used to model chronic dosing paradigm, and steady state fasudil levels in transgenic
mouse brains under variable dosing paradigms will be established. Aim 2.To determine PD of fasudil and
establish PK-PD relationship in transgenic mice. We will quantify brain levels of Aβ (Aβ38, 40, 42), total
Tau, and pTau in 3X-Tg AD transgenic mice after a single dose of fasudil as well as multiple doses of fasudil
over a two-week interval. We will determine efficacy of chronic fasudil dosing on memory tests performed on
transgenic mice and establish PK-PD relationship and calculate the therapeutic index. Aim 3. To determine
the mechanism of action for effect of fasudil on Aβ/Tau/pTau. We will examine the effect of fasudil on the
Wnt-β-cat and Wnt-PCP pathways and phosphorylation of Tau. In addition, we will establish a causative
relationship between regulation of Wnt pathway and reduction of Aβ/Tau/pTau. We will measure the dose-
dependent impact of fasudil on β-catenin, p-β-catenin, and promoter assays for both Wnt pathways. Results
will be correlated with reduction of Aβ/Tau/pTau. We will also activate the Wnt-PCP pathway in HEK293 cells
with Dkk1 and then treat with fasudil to determine the effect of fasudil on Aβ/Tau/pTau during PCP Wnt
ac tivation.

## Key facts

- **NIH application ID:** 10438540
- **Project number:** 5I01BX004730-03
- **Recipient organization:** EDITH NOURSE  ROGERS MEMORIAL VETERANS HOSPITAL
- **Principal Investigator:** Peter Morin Morin
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10438540

## Citation

> US National Institutes of Health, RePORTER application 10438540, Exploring Alzheimer Therapeutics (5I01BX004730-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10438540. Licensed CC0.

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