Optogenetic Regulation of Phosphoinositide Metabolism in Susceptibility, Resistance, and Resiliency to Alzheimer's Disease-Associated Deficits and Pathology
Abstract
Lipid dyshomeostasis in Alzheimers disease (AD) has been reported for over 30 years, but recent advances in the sensitivity and quantitative accuracy of system level lipidomics have allowed for broader interpretation of dysregulated lipid metabolism. Our lab has demonstrated that a phosphoinositide (PI) signaling lipid, phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] is depleted in human AD affected brain as well as in animal models of the disease. Genetic disruption of a major PI(4,5)P2 degrading enzyme, Synaptojanin1, ameliorated lipid imbalance and rescued AD-associated deficits in cognition and amyloid beta-peptide (A-beta) induced synapses loss in a mouse model. Single nucleotide polymorphoisms in Synj1 have been shown to be associated with age of onset of AD. We hypothesize that a temporally and spatially specific change in PI(4,5)P2, representing a more physiologically and therapeutically relevant paradigm, will restore cognitive and synaptic function and validate phosphoinositide (PI) metabolism as a necessary and sufficient determinant for susceptibility to AD behavioral and synaptic deficits. Optogenetic tools for enriching or depleting PI(4,5)P2 have been described in cell lines in vitro, but have not yet been demonstrated in vivo. Specific Aim 1: We will test the hypothesis that optogenetically mediated enrichment of phosphoinositide levels in mouse brain will ameliorate AD associated behavioral deficits in chronic and acute mouse models of AD-associated cognitive and synaptic deficits. We have successfully subcloned the catalytic domain of optogenetically activated PI kinases. We will administer the viral vector into mouse hippocampi to enrich PI(4,5)P2 and test for amelioration of behavioral and synaptic deficits associated with AD. We will use a genetic mouse model overexpressing the amyloid precursor protein with the Swedish mutation (Tg2576) as well as an acute model of A-beta-infusion directly into the hippocampi of freely behaving animals.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2021
- Accession Number
- AD1162173
Entities
People
- Laura B. Mcintire
Organizations
- Columbia University