Joshua Kulas

Date of Award

January 2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

First Advisor

Colin K. Combs

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease in which the brain progressively deteriorates resulting in cognitive decline, language impairment, diminished spatial awareness, memory loss and ultimately, death. AD is the most prevalent neurodegenerative disease and the number of people afflicted by AD is expected to more than double in the next 30 years. AD is characterized in part by the formation of amyloid plaque deposits in the brain. It is known that these plaques are composed of the peptide Aβ, which aggregates as a function of age and is produced locally within the brain by cleavage of the Amyloid precursor protein (APP). It is now recognized that type 2 diabetes is a risk factor for the development AD and the AD brain has impaired insulin signaling. Transgenic mice lacking the APP gene show broad changes in metabolism, suggesting APP may play an important in regulating metabolic homeostasis. This dissertation consists of two central studies aimed at understanding the relationship between APP and insulin signaling. The first aim is to examine the role APP plays in plaque formation within the pancreas and to understand APP’s contribution to endocrine pancreas physiology. The second aim is to examine the role APP plays in the regulation of the Insulin Degrading Enzyme (IDE).

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