Date of Degree

9-30-2017

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biochemistry

Advisor(s)

Maria E. Figueiredo-Pereira

Committee Members

Patricia Rockwell

Thomas Schmidt-Glenewinkel

Peter Serrano

Nikolaos K Robakis

Carol Troy

Subject Categories

Behavioral Neurobiology | Biochemistry | Molecular and Cellular Neuroscience

Keywords

Amyloid Precursor Protein, Alzheimer's Disease, Cyclooxygenase Pathway, Prostaglandin J2, O-GlcNAcylation

Abstract

Inflammation plays a major role in Alzheimer’s disease (AD). Investigating how specific mediators of inflammation contribute to neurodegeneration in AD is crucial. Our studies focused on cyclooxygenases, which are key enzymes in inflammation and highly relevant to AD. Cyclooxygenases (COX -1, constitutive; COX-2, inducible) have emerged as important determinants of AD pathogenesis and progression. COX-2 is highly induced in AD, correlating with AD severity, and COX-1 is also involved in AD. Cyclooxygenases are the rate-limiting enzymes that convert arachidonic acid into prostaglandins (PGs), the principal mediators of CNS neuroinflammation.

The overall GOAL of these studies was to address the mechanisms by which the neurotoxic prostaglandin J2 (PGJ2) contributes to the pathophysiology of AD.

In rodents, stroke (cerebral ischemia) and traumatic brain injury (TBI) elevate PGJ2 levels in the brain to concentrations similar to those shown to be neurotoxic in vitro. Stroke and TBI increase the long-term risk for AD through mechanisms that are unknown. Thus, the studies presented in this dissertation specifically investigated mechanisms induced by PGJ2 relevant to AD pathology. To achieve our GOAL we carried-out two specific aims:

Specific aim 1: Determine the effects of PGJ2 on processing of the amyloid precursor protein (APP) in neuronal cells.

Specific AIM 2: Investigate the effects of PGJ2 on the progression of molecular and behavioral pathology in the 3xTg-AD mouse model of AD.

Targeting prostaglandins such as PGJ2 that mediate neurodegeneration downstream from cyclooxygenases, is a novel therapeutic strategy that could improve clinical outcomes with fewer side effects. This global strategy is applicable to AD and other neurological disorders in which the cyclooxygenase pathway of inflammation plays a critical role.

 
 

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