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. 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 will determine if there is a correlation between phosphoinositide levels in human brain, plasma and CSF with AD age of onset (susceptibility) leading to potential identification of a novel biomarker for AD susceptibility. We have been working closely with the IRB as well as Dr. James Noble to obtain approval for use of human derived biospecimens for lipidomic studies.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2023
- Accession Number
- AD1226978
Entities
People
- Abid Hussaini
- Laura B. Mcintire
Organizations
- Columbia University