# Mechanisms and therapeutics of calcium dysregulation and synapse loss in Alzheimer's disease

> **NIH NIH R21** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $211,875

## Abstract

The goal of this proposal is to elucidate the mechanisms underlying calcium dysregulation and synapse loss in
mouse models of Alzheimer's disease (AD). Many lines of evidence have shown that synapse loss occurs early
in AD pathogenesis and is the best correlate of cognitive impairment in AD patients. Despite much effort, the
mechanisms underlying synaptic loss in AD remain unclear. We have recently found that the dendrites of layer
2/3 pyramidal neurons exhibit abnormally long duration, high amplitude Ca2+ spikes in the APPPS1 mouse model
of AD. The prolonged dendritic Ca2+ spikes are associated with the reduction in synaptic activity and size in this
mouse model. By employing in vivo imaging, molecular and pharmacological approaches, we propose to
determine whether the generation of abnormal dendritic Ca2+ spikes and their detrimental impact on synapse
loss are a general phenomenon in mice carrying APP and PS1 mutations. Our preliminary studies show that
NMDA receptor-dependent production of cyclic GMP and activation of the cyclic GMP regulated kinase II (cGKII)
regulate the release of Ca2+ from endoplasmic reticulum to the cytosol. We will determine the important role of
this cGKII-dependent signaling pathway in the generation of long-duration dendritic Ca2+ spikes in APP and PS1
mutant mice. To alleviate the generation of abnormal long-duration dendritic Ca2+ spikes and their detrimental
consequences on synaptic plasticity, we will investigate the impact of reducing cGKII activity either by genetic or
pharmacological manipulations in APP and PS1 mutant mice. The proposed experiments will reveal the
mechanisms underlying the generation of abnormal dendritic Ca2+ spikes and their impact on synapse loss in
AD. The proposed studies will also generate important new insights into the therapeutic treatment of AD aiming
at reducing calcium dysregulation and synapse loss with cGKII inhibitors.

## Key facts

- **NIH application ID:** 9988342
- **Project number:** 5R21AG064273-02
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** WENBIAO GAN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $211,875
- **Award type:** 5
- **Project period:** 2019-08-15 → 2022-04-23

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988342

## Citation

> US National Institutes of Health, RePORTER application 9988342, Mechanisms and therapeutics of calcium dysregulation and synapse loss in Alzheimer's disease (5R21AG064273-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9988342. Licensed CC0.

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