The goal of this proposal is to establish the link among stress, Ca2+ dysregulation and synapse loss in aging and a mouse model of Alzheimer's disease (AD). AD is the most common cause of dementia in the elderly. Synapse loss occurs many years before dementia and is the best correlate of cognitive impairment in AD patients. In the APPPS1 mouse model of AD, we have recently found that a fraction of dendrites of pyramidal neurons exhibit abnormal high-amplitude long-duration dendritic Ca2+ spikes, which result in synaptic depotentiation. We have also found that the deletion of glucocorticoid receptors (GR) phosphorylation at brain-derived neurotrophic factor (BDNF)-responding sites increases the amplitude and frequency of dendritic Ca2+ spikes. Based on these findings, we propose to test the hypothesis that stress hormone glucocorticoids promote abnormal dendritic Ca2+ spikes and lead to synaptic dysfunction and loss while BDNF reduces these detrimental effects by affecting GR phosphorylation and its signaling pathway. To alleviate the generation of abnormal dendritic Ca2+ spikes and their detrimental consequences on synaptic plasticity, we will investigate the impact of reducing stress hormone glucocorticoids or increasing BDNF activity by genetic or pharmacological manipulations in the AD mouse model. The proposed experiments will determine the role of stress in the generation of abnormal dendritic Ca2+ spikes and synapse loss in aging and AD pathogenesis. The proposed studies will also generate important new insights into the therapeutic treatment of AD aiming at reducing stress, Ca2+ dysregulation and synapse loss.
Alzheimer?s disease (AD) is a major health problem worldwide. Stress is thought to contribute to memory and learning impairment in the early stages of AD. In this proposal, we will determine the role of stress hormone glucocorticoids in the dysregulation of calcium and loss of neuronal connections in aging and a mouse model of AD. We will also test pharmacological treatments for reducing stress effects and preventing loss of neuronal connections in the mouse AD model.
