A Healthy Brain Aging Strategy to Restore Insulin Signaling and Ca2+ Homeostasis

Peripheral metabolic dysregulation alters cognitive function with aging and appears to increase susceptibility to dementing neurodegenerative disorders such as Alzheimer’s disease. However, the pathways and mechanisms underlying the relationship between metabolic dysregulation, aging and impaired cognition are not yet clear. Here we propose that one of the main actions of insulin on hippocampal neurons is beneficial and helps reestablish calcium homeostasis in the aging brain. Indeed, age-related calcium dysregulation has been well characterized in brain structures including the hippocampus, and is strongly linked to neurologic dysfunction, cognitive decline, and disease. Preliminary data and work accomplished in the previous funding cycle identified an unrecognized link between metabolic dysregulation and altered calcium signaling in hippocampal neurons. Based on these observations, the proposed systematic studies will investigate mechanisms underlying the beneficial impact of elevating insulin signaling in the brain of aged animals with a particular focus on normalizing calcium homeostasis. Our approach includes 3 phases whereby we will 1) utilize intranasal insulin delivery to increase insulin availability at the brain insulin receptor in vivo, 2) increase insulin receptor signaling in the brain via AAV-mediated expression of a constitutively active human insulin receptor mutant (? subunit), and 3) increase endogenous insulin receptor trafficking through the use of a novel pharmacologic strategy. Hippocampal calcium regulation (direct calcium imaging, recordings of calcium-dependent potentials), glucose signaling (direct glucose imaging), neuronal function, and cognitive status will be assessed in the F344 animal model of aging. Each Aim will use a comprehensive set of techniques from single cell imaging (calcium, glucose), to single cell electrophysiology, Morris water maze testing, and an assortment of molecular/biochemical assays (e.g., biotinylation, Westerns, AAV, nCounter). It is estimated that 90% of diabetics in the USA today are type 2 diabetics (e.g., late-onset diabetes), accounting for approximately 26 million people and a $175 billion dollar toll to our health care system (CDC statistics). Our long-term goals are designed to enhance insulin signaling and reduce cognitive decline in aging in order to maintain healthy cognitive function with age. The approach will benefit the aging population, and by extension, reduce the driving force on neurodegenerative diseases that share common mechanisms with brain aging (e.g., Alzheimer’s disease). We propose that maintaining insulin signaling using intranasal delivery of different insulin preparations and regimens, together with molecular and pharmacological approaches for increasing insulin receptor function, will prevent or reduce neuronal Ca2+ dysregulation with aging. This work is clinically-oriented and directly addresses one of the missions of the NIA by establishing novel targets for the treatment of cognitive decline and/or dementia in brain aging.