Optogenetic Regulation of Phosphoinositide Metabolism in Susceptibility, Resistance, and Resiliency to Alzheimers Disease-Associated Deficits and Pathology
Abstract
Alterations to lipids and biological membranes are emerging as early and critically dysregulated contributors to Alzheimer’s disease (AD) pathogenesis. Multiple genetic studies have shown variants that either increase or decrease risk for AD development. The genetic variant with the greatest effect on AD risk is apolipoprotein E (ApoE), which can increase risk for developing AD 12-fold for carriers of the variant. ApoE is known to be involved in cholesterol transport in the brain. The second strongest effect on AD risk is elicited by a variant in Bridging Integrator 1 (BIN1). The role for BIN1 is still under investigation; however, we know it binds and is likely to functionally interact with Synaptojanin 1 (Synj1), a lipid phosphatase in the brain. Synaptojanin 1 is known to regulate the levels of the important signaling lipid phosphatidylinositol 4,5-bisphosphate (PIP2). Our work, and the work of others, has shown PIP2 is depleted in mouse models of disease and in AD patient brain tissue. Using a mouse model of the disease, we showed that genetically altering Synj1, and the resulting change in PIP2, was able to rescue multiple behavioral phenotypes in an animal model of AD. We also showed that the same genetic alteration of Synj1 was able to prevent synapse loss and maintain normal neuronal function. We hypothesize that Synj1 regulation of PIP2 levels is critical in AD and may be able to prevent or restore normal neuronal functioning in the brain. We propose to manipulate the levels of PIP2 in live animals using optogenetics, which is the stimulation of genetically encoded proteins using blue light. We will express proteins known to increase PIP2 levels in the brain in live animals, stimulate the activity of the protein, and determine if behavioral deficits in animal models of the disease are ameliorated. We will also quantify the levels of PIP2 in the brain of the animals to determine if the protein expression was successful. In order to corroborate the importance of lipid regulation in AD, we will quantify the level of phosphoinositide (PI) and other lipids in biofluids and tissue from AD patients and controls. We will use matched samples from individual patients to determine the whole body changes in lipid levels and correlate them with age of onset for AD. For these studies, we will use the powerful technology of targeted lipid“omics,” which is in its infancy compared to gen“omics,” but is emerging as an equally powerful tool for biological research. Our studies have potential to determine if levels of PIP2 (or other lipids) may lead to susceptibility to development of AD and could be used in the future as biomarkers of the disease risk. We will also determine whether stimulation of PIP2 in live animals can lead to amelioration of behavioral deficits in learning and memory. These studies will validate the potential for PIP2 levels to act preventatively to slow progression to AD as well as evaluate the ability of PIP2 restoration for amelioration of AD-associated cognitive deficits. These studies also have potential to identify PIP2 manipulation as a promising target for prevention of AD conversion after traumatic brain injury.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910817
Entities
People
- Laura Beth Mcintire
Organizations
- Columbia University
- United States Army