Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Anatomy and Cell Biology

Supervisor

Whitehead, Shawn N.

2nd Supervisor

Cechetto, David F.

Co-Supervisor

Abstract

Gangliosides are a family of membrane lipids enriched in the central nervous system (CNS) that play an important role in cell signaling processes on the membrane. Alterations in the homeostatic distribution of the a-series family of gangliosides has been observed in both pre-clinical models and human patients with neurodegenerative diseases and injuries, such as Alzheimer’s disease (AD) and strokes. Ganglioside dysregulation has been implicated as an important mechanisms driving pathology in the aging brain, yet there is little information on where and when these lipid changes occur as well as the role of dysregulation during neurodegeneration. Matrix-Assisted Laser Desorption/Ionization (MALDI) imaging mass spectrometry (IMS) is a novel imaging technique that can map the distribution of ionizable molecules on a sample in a 2-dimensional format, making it the ideal tool for analyzing gangliosides on post-mortem brain tissue sections. A comorbid rat model of stroke and Aβ toxicity, using an endothelin-1 (ET-1) induced unilateral striatal stroke together with intracerebralventricular (icv) injections of Aβ(25-35), was used to examine ganglioside dysregulation in response to neurodegenerative injuries of varying severity. Results indicated that ganglioside dysregulation was correlated with the severity of the neurodegenerative injury and showed a characteristic pattern of depleted protective complex gangliosides with accumulated toxic simple gangliosides at the site of injury. Transgenic (Tg) rats with a mutation in the Alzheimer’s precursor protein (APP) demonstrated a similar characteristic shift in ganglioside distribution during aging compared to wild-type (Wt) rats in brain regions which are susceptible to damage in AD, such as the white matter and hippocampus. Finally, chloroquine (CQ), a pharmacological inhibitor of ganglioside catabolism, was used as a treatment for ganglioside dysregulation after injury in the rat comorbid stroke model. CQ was found to prevent ganglioside dysregulation acutely after stroke and was correlated with reduced pathology and functional impairments. These results support the hypothesis of ganglioside dysregulation as an important mechanism of neurodegeneration in the aging and injured brain and highlights the benefits associated with the restoration of ganglioside homeostasis after stroke injury.

Available for download on Friday, February 01, 2019

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