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.
Alzheimer?s disease is a major health problem worldwide, marked by memory loss and cognitive decline. In this proposal we will study the role of deregulation of calcium in causing abnormal neuronal changes in mouse models for Familial Alzheimer?s Disease (FAD). We will also test pharmacological treatments for their ability to restore normal calcium metabolism and learning and memory formation in these mouse models.
