# Mechanisms of Dantrolene Neuroprotection in Alzheimer's Disease

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $402,500

## Abstract

Abstract
 Clinical trials for the treatment of Alzheimer's disease (AD) targeting amyloid have
largely failed. Ca2+ dysregulation may be an alternative mechanism. In familial AD (FAD),
calcium homeostasis is disrupted by over activation of NMDA (NMDAR) and ryanodine (RYR)
receptors leading to increased cytosolic calcium and subsequent cognitive dysfunction and
neuropathology. APOE4, a major risk factor for sporadic AD (SAD), also causes Ca2+
dysregulation related to NMDAR/RYR over activation. Dantrolene, a RYR antagonist and
clinically available drug, has been shown to mitigate amyloid pathology, neurodegeneration,
synaptic and memory loss in a FAD animal model. Our preliminary studies suggested that
intranasal dantrolene administration abolished memory loss in 5XFAD mice. Furthermore,
dantrolene promoted neuronal differentiation in induced pluripotent stem cells (iPSC) from
patients with either SAD with APOE4 or familial AD (FAD) by inhibition of RYR/NMDAR over-
activation. Our long term goal is to examine the efficacy of dantrolene to treat AD. The overall
objective of this study is to investigate the effects and underlying mechanisms of dantrolene on
adult neurogenesis in human and rodent SAD and FAD cells, as well as the effects of intranasal
dantrolene administration on adult neurogenesis and cognitive function in AD transgenic mice.
Our central hypothesis is that intranasal dantrolene inhibits the excessive activation of
RYRs and NMDARs in AD and promotes adult neurogenesis, improved cognitive function
and reduced AD neuropathology. We will test the hypothesis by the following specific aims.
Specific Aim 1. To determine the effects of dantrolene on RYR and NMDAR expression
and on cytosolic, mitochondrial, and ER Ca2+ concentrations and AD biomarkers in AD
stem cells using induced pluripotent stem cells (iPSC) from fibroblasts patients with either SAD
(APOE4 risk factor) or FAD (PSEN1 mutations), as well as neuroprogenitor cells (NPC) isolated
from E4FAD (APOE4+5XFAD) and 5XFAD transgenic Specific Aim 2. To examine the effects
of dantrolene on RYR and NMDAR activity, neurogenesis, proliferation, and the cellular
function of derived neurons and glia from AD cells. using the same cells as in SA1.
Specific Aim 3. To determine the effects of dantrolene on adult neurogenesis, cognitive
function, and neuropathology in animal models of AD. We expect that dantrolene will
promote adult neurogenesis and restore cognition and reduce AD pathology in AD mouse
models by alleviating the excessive activation of RYRs and/or NMDARs, especially with the
intranasal approach.

## Key facts

- **NIH application ID:** 10343664
- **Project number:** 5R01AG061447-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** HUAFENG WEI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $402,500
- **Award type:** 5
- **Project period:** 2019-03-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10343664

## Citation

> US National Institutes of Health, RePORTER application 10343664, Mechanisms of Dantrolene Neuroprotection in Alzheimer's Disease (5R01AG061447-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10343664. Licensed CC0.

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