Peripheral metabolic dysregulation appears to increase the risk for cognitive decline with aging and susceptibility to dementing neurodegenerative disorders such as Alzheimer's disease. However, the pathways and mechanisms underlying the relationship between metabolic dysregulation and age-related cognitive impairment are not clearly defined. Here we propose that insulin resistance in the brain can destabilize tightly regulated processes which maintain normal calcium homeostasis in neurons resulting in neuronal dysfunction and impaired cognition. Age-related neuronal calcium dysregulation is a well-recognized mechanism contributing to neurologic dysfunction and cognitive decline and we and others have extensively characterized this dysfunction in brain structures important for learning and memory. Interestingly, peripheral tissues that are insulin resistant also show calcium dysregulation and provide supporting evidence for a similar relationship in the brain. In the prior funding cycle, we identified a previously unrecognized link between metabolic dysregulation and altered calcium signaling in hippocampal neurons. Together, these findings provide support for the notion that overcoming insulin resistance in the hippocampus with insulin-raising strategies will reestablish neuronal calcium homeostasis. Several innovative approaches will be used to increase brain insulin signaling in aging. Specifically, we will 1) utilize intranasal insulin delivery to increas insulin availability at the brain insulin receptor in vivo, 2) increase insulin receptor signaling n 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. Using these approaches in the F344 rat model of aging, we will investigate cognitive functions using different behavioral paradigms. In hippocampal tissue from these animals, we will use single cell electrophysiology/imaging to directly measure calcium status (recordings of calcium-dependent potentials and calcium imaging), and complement these studies with molecular/biochemical assays. To determine whether increasing insulin in the brain affects other pathways independent of Ca2+, we will also quantify p-Akt signaling, tyrosine phosphorylation, glucose homeostasis (glucose imaging), and adiponectin levels. Type 2 diabetes has reached epidemic proportions among older adults accounting for approximately 26 million people and a $175 billion dollar toll to our health care system (CDC statistics). Our studies are designed to determine whether enhancing insulin action in the brain reduces the burden of cognitive decline in aging and helps to maintain healthy cognitive function. The outcomes from our studies will inform related clinical studies and may have significant impact for the aging population, especially for those at increased risk for neurodegenerative diseases such as Alzheimer's disease. 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.

Public Health Relevance

Our work will test if the mechanism of insulin actions in the brain modulates calcium-related functions inside cells. We will focus on one area of the brain that is known for its role in memory function, the hippocampus. We propose new ways to increase insulin signals in the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG033649-08
Application #
9256396
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Wise, Bradley C
Project Start
2009-08-01
Project End
2020-03-31
Budget Start
2017-05-01
Budget End
2018-03-31
Support Year
8
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40526
Hampton, Kaia K; Anderson, Katie; Frazier, Hilaree et al. (2018) Insulin Receptor Plasma Membrane Levels Increased by the Progesterone Receptor Membrane Component 1. Mol Pharmacol 94:665-673
Frazier, H N; Anderson, K L; Maimaiti, S et al. (2018) Expression of a Constitutively Active Human Insulin Receptor in Hippocampal Neurons Does Not Alter VGCC Currents. Neurochem Res :
Gant, John C; Blalock, Eric M; Chen, Kuey-Chu et al. (2018) FK506-Binding Protein 12.6/1b, a Negative Regulator of [Ca2+], Rescues Memory and Restores Genomic Regulation in the Hippocampus of Aging Rats. J Neurosci 38:1030-1041
Frazier, Hilaree N; Maimaiti, Shaniya; Anderson, Katie L et al. (2017) Calcium's role as nuanced modulator of cellular physiology in the brain. Biochem Biophys Res Commun 483:981-987
Berkowitz, Bruce A; Lenning, Jacob; Khetarpal, Nikita et al. (2017) In vivo imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome. FASEB J 31:4179-4186
Maimaiti, Shaniya; Frazier, Hilaree N; Anderson, Katie L et al. (2017) Novel calcium-related targets of insulin in hippocampal neurons. Neuroscience 364:130-142
Anderson, Katie L; Frazier, Hilaree N; Maimaiti, Shaniya et al. (2017) Impact of Single or Repeated Dose Intranasal Zinc-free Insulin in Young and Aged F344 Rats on Cognition, Signaling, and Brain Metabolism. J Gerontol A Biol Sci Med Sci 72:189-197
Maimaiti, Shaniya; Anderson, Katie L; DeMoll, Chris et al. (2016) Intranasal Insulin Improves Age-Related Cognitive Deficits and Reverses Electrophysiological Correlates of Brain Aging. J Gerontol A Biol Sci Med Sci 71:30-9
Maimaiti, Shaniya; DeMoll, Chris; Anderson, Katie L et al. (2015) Short-lived diabetes in the young-adult ZDF rat does not exacerbate neuronal Ca(2+) biomarkers of aging. Brain Res 1621:214-21
Latimer, Caitlin S; Brewer, Lawrence D; Searcy, James L et al. (2014) Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats. Proc Natl Acad Sci U S A 111:E4359-66

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