College of Science and Health Theses and Dissertations

Date of Award

Spring 6-8-2018

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Biology

First Advisor

Eric Norstrom, PhD

Second Advisor

Sarah Connolly, PhD

Third Advisor

Dorothy Kozlowski, PhD

Abstract

Alzheimer’s disease (AD) is the leading form of dementia worldwide. It is associated with advanced age and involves a progressive cognitive decline. Pathologically, AD is characterized by two defining features: neurofibrillary tangles and amyloid plaques. The neurofibrillary tangles are composed of cleaved and hyperphosphorylated forms of the protein tau. The amyloid plaques are aggregates of the amyloid β (Aβ) peptide. Aβ is derived from a larger precursor protein, the amyloid precursor protein (APP), through sequential proteolytic cleavages. APP can first be enzymatically cleaved by either α- or β-secretase. If first cleaved by α-secretase, it is cleaved within its Aβ domain; therefore, the formation of Aβ is precluded. If first cleaved by β-secretase, subsequent cleavage by γ-secretase results in the production of differentially sized Aβ peptides of 40-42 amino acids that can accumulate to form the characteristic plaques of the disorder. Since genetic evidence indicates that Aβ accumulation is the primary causative agent of AD, much emphasis has been placed on elucidating factors that influence its formation. My thesis will discuss the impact of one such influential factor: the growth-associated protein-43 (GAP-43). I found that overexpression of GAP-43 and APP in HEK293 cells, a human embryonic kidney cell line, results in a profound decrease in the processing of APP by both α- and β-secretase and that this effect is dependent on the palmitoylation of cysteines 3 and 4 of GAP-43. To our knowledge, this paper is the first known report to describe a functional interaction between APP and GAP-43. By shedding light on factors that play a crucial role in determining the processing fate of APP, we bring ourselves closer in the search for an effective therapy for the treatment of AD.

SLP Collection

no

Download

Included in

Biology Commons

Share

COinS