Calcium signaling and autophagy defects in Alzheimer's disease neurons

ABSTRACT The broad, long-term objective of this grant application is to understand the mechanisms responsible for autophagy defects in neurons affected by Alzheimer’s disease (AD). Dysregulation of neuronal autophagy play important role in AD pathogenesis from the studies of both AD patients and animal models. Dysfunctional calcium (Ca2+) signaling is also a well-established driver of AD pathology. Based on results recently obtained by our laboratory we proposed a model that casually connects dysregulation of neuronal Ca2+, impaired autophagy and AD pathology. The main aim of this grant proposal is to test this novel hypothesis. To test this hypothesis, we will perform experiments with transgenic AD mouse model and will evaluate effects of (1) clinically relevant ryanodine receptor type 2 (RyanR2) inhibitors; (2) positive allosteric modulators of the sarco- endoplasmic reticulum calcium ATPase (SERCA); (3) dominant-negative constructs targeting Serine/Threonine kinase 11 interacting protein (STK11IP). In our measurements we quantify ability of these manipulations to rescue defects in neuronal autophagy and to exert synaptoprotective and neuroprotective effects. Results obtained in the proposed studies will provide essential information regarding connection between Ca2+ signaling and autophagy defects and AD, help to validate novel therapeutic targets for AD treatment and also provide information about potential lead molecules for development of AD therapeutic agents.