Date of Award




Document Type


Degree Name

Doctor of Philosophy (PhD)


Department of Psychology


Behavioral Neuroscience

Content Description

1 online resource (v, 115 pages) : illustrations (some color)

Dissertation/Thesis Chair

Ewan C McNay

Committee Members

Robert W Flint, Christine K Wagner, Bruce C Dudek


Angiotensin IV, Cognitive enhancement, Glucose, GluT4, hippocampus, Alzheimer's disease, Angiotensins, Nootropic agents

Subject Categories

Biological Psychology | Psychology


Alzheimer's disease (AD) is a progressive neurodegenerative disorder, characterized behaviorally by profound cognitive impairment. Currently, there is no cure for this disorder and available therapeutics only slow the progression of cognitive decline in a subset of the AD population Recent research has shifted to upregulation of the insulin signaling pathway as a mechanism to restore cognition in the AD population, as this system is known to be impaired in the AD brain. A possible novel therapeutic for the treatment of cognitive impairment is Angiotensin IV (Ang IV). Ang IV is an endogenous pentapeptide inhibitor of the insulin-regulated aminopeptidase (IRAP) and the last known active metabolite in the Renin Angiotensin System (RAS). Distributed throughout the brain, predominately in structures important to cognitive processing such as the hippocampus and amygdala, IRAP inactivation via Ang IV binding has the ability to enhance cognition in controls and restore cognition in impaired animals. Despite the ability of Ang IV to enhance cognition, its mechanism of action remains unknown. Within the hippocampus IRAP is highly colocalized and redistributes with GluT4 to the plasma membrane in response to insulin. Moreover, Ang IV has the ability to enhance potassium induced-depolarization and cAMP activated glucose uptake in hippocampal slices, yet translating and extending these findings to an in vivo model has proven difficult despite the well-accepted ability of Ang IV to enhance cognition. Without a concrete mechanism or specific site of action, it is unknown whether this agent will be efficacious in a diseased brain, especially one with impaired insulin signaling, to produce cognitive enhancement and/or restoration. Initial exploration of the underlying mechanisms by which Ang IV enhances cognition in control brains should first be explored in the progression toward human trials. This dissertation will test the overarching hypotheses (i) that the hippocampus is a primary site of action for cognitive enhancement by Ang IV/Nle1-Ang IV and (ii) that increased GluT4-dependendent glucose is the primary mechanism of action by which Ang IV enhances cognition within the hippocampus.