Calcium signaling and synaptic maintenance in Alzheimers disease

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The broad, long-term objective of this multi-PI grant application is to understand the importance of calcium (Ca2+) signaling for synaptic spine dysfunction and loss in Alzheimer's disease (AD). Understanding the molecular mechanisms that lead to initial synaptic dysfunction and synapse loss in AD is essential for early disease detection as well as for the development of effective therapeutic interventions. However, primary steps that result in synaptic dysfunction and loss in AD remain poorly understood. There is an increasing consensus that alterations in neuronal Ca2+ signaling is a key contributor to the pathogenesis of AD, however, the impact of these Ca2+ signaling alterations on long term synapse homeostasis and control of synapse stability is unclear. In our studies we will focus on two major neuronal Ca2+ signaling pathways - neuronal store-operated Ca2+ entry (SOC) pathway and Ca2+ influx via NMDAR driven by spontaneous vesicle release (SVR) from the presynaptic terminals. Both of these pathways are active chronically and maintain baseline synaptic Ca2+ signals. Working independently, our two groups have identified key Ca2+ signaling pathways that are active chronically and maintain synapse stability We will investigate roles played by these pathways in synaptic maintenance and analyze dysregulation of these pathways in neurons from AD mouse models. Specifically, we will (1) investigate the role of spontaneous glutamate release-mediated NMDAR signaling in AD-related alterations in hippocampal synaptic Ca2+ homeostasis. Spontaneous glutamate release-mediated Ca2+ signaling measurements will be performed with primary neuronal cultures from presenilin 1 M146V knock-in (PS1KI) and APP knock-in (APPKI) mouse models; (2) investigate the changes in synaptic Ca2+ homeostatic mechanisms in AD neurons. We will test the hypothesis that a balance in activity of CaMKII and Calcineurin (CaN) is shifted in synaptic spines of AD neurons, leading to synaptic loss; (3) evaluate synaptic Ca2+ homeostatic mechanisms as potential target for AD treatment. Pharmacological and genetic experiments will be performed in this aim. Results obtained in our studies provide essential mechanistic information about causes of synaptic loss in AD and offer new potential therapeutic targets for treatment of AD.