Shilling, Dustin J
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PublicationExaminations into the Calcium Hypothesis of Alzheimer's Disease(2013-01-01) Shilling, Dustin JAlzheimer's disease (AD) is devastating to the patient, their family and friends, and represents a significant fiscal burden to our society. Currently available therapeutics provide only mild symptomatic relief and do not alter the course of the disease. Developing the next generation of disease modifying therapies requires an understanding of the early cellular changes responsible for AD. A hindrance to progress is the fact that most patients develop AD sporadically. However, mutations in the presenilin (PS) homologs cause dominantly inherited, early-onset AD. These mutations provide an important tool for understanding the cellular changes that cause AD. One consequence of PS mutations is exaggerated intracellular Ca2+ ([Ca2+]i) signaling. However, the mechanisms underlying this phenomenon remain controversial and its role in AD pathogenesis is unknown. Presented here are data indicating that exaggerated [Ca2+]i signaling is dependent upon the inositol 1,4,5-trisphosphate receptor (InsP3R) and contributes to AD pathogenesis in vivo. We began our studies by testing multiple proposed mechanisms for exaggerated [Ca2+]i signaling. To do this we employed multiple Ca2+ imaging protocols and Ca2+ indicators to directly measure ER Ca2+ dynamics in several cell systems. We found that decreasing InsP3R protein level rescues exaggerated [Ca2+]i signaling in primary cortical neurons and hippocampal slices from mutant PS1 expressing mice. We then determined the contribution of exaggerated [Ca2+]i signaling to AD pathogenesis. Using a combination of genetic, biochemical, electrophysiological and behavioral techniques, we found that rescue of exaggerated [Ca2+]i signaling dramatically attenuates mild cognitive impairment and AD phenotypes in AD mouse models. Reduction of InsP3R1 protein level in PS1M146V-KIN mice rescued enhanced hippocampal ryanodine receptor protein level, enhanced hippocampal synaptic potentiation, and constitutive activation of the CaMKIV-CREB transcriptional pathway. In 3xTg mice, reduced InsP3R1 protein level attenuated Aβ and phospho-tau accumulation and hippocampal electrophysiology and memory impairments. Together, these results reveal that mutant PS-associated exaggerated [Ca2+]i signaling is InsP3R1-dependent, a proximal event, and contributes to the development of AD in vivo. These findings advance our understanding of the pathological role of exaggerated [Ca2+]i signaling in AD and identify several novel targets for the development of disease modifying therapeutics.