Optogenetic Regulation of Phosphoinositide Metabolism in Susceptibility, Resistance, and Resiliency to Alzheimer's Disease-Associated Deficits and Pathology
Abstract
Lipid dyshomeostasis in Alzheimer's 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2020
- Accession Number
- AD1121022
Entities
People
- Laura B. Mcintire
Organizations
- Columbia University