Date of Award

2021

Embargo Period

4-23-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neurology

College

College of Graduate Studies

First Advisor

Catrina Sims-Robinson

Second Advisor

Lauren Ball

Third Advisor

Andreana Benitez

Fourth Advisor

Robin Muise-Helmericks

Fifth Advisor

Paula Traktman

Abstract

Over 93 million Americans are obese, a condition which also increases the risk for developing neurocognitive disorders such as Alzheimer’s disease. Insulin is critically important for maintaining homeostasis in the central nervous system, but in order to play this role it has to be transported in from the periphery. Interestingly, peripheral hyperinsulinemia is linked to reduced central nervous system insulin. The overarching hypothesis of this dissertation is that chronic hyperinsulinemia reduces hippocampal insulin transport, thereby dysregulating insulin receptor signaling proteins and leading to memory impairment. In order to test this hypothesis, we assessed the high-fat diet mouse model in two hippocampal-dependent memory tasks. Hippocampi isolated from high-fat diet fed mice were probed for insulin levels and signs of insulin resistance. Hippocampal microvessels were also isolated and probed for dysfunction of the insulin receptor. These latter studies were followed up through in vitro mechanistic analysis of the insulin receptor during experimental hyperinsulinemia. Our findings indicate that high-fat diet feeding leads to hippocampal-dependent memory impairment and dysfunctional changes in the hippocampal insulin signaling cascade. Our hyperinsulinemic brain endothelial cell studies suggest that impaired insulin receptor functioning at this barrier underlies impaired receptor internalization, a key step in the transcytosis mechanism. Interestingly, inhibition of a major negative modulator of the insulin receptor signaling system in brain endothelial cells improved receptor functioning, indicating this as a potential therapeutic target going forward. In conclusion, the consequences of peripheral hyperinsulinemia may be an important mechanism connecting obesity with memory impairment and Alzheimer’s disease, and reversing impairment of the brain microvascular insulin receptor may be a potentially novel therapeutic approach.

Rights

All rights reserved. Copyright is held by the author.

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