Master of Science
Anatomy and Cell Biology
Dr. Shawn Whitehead
Accumulation of beta-amyloid (Aβ) in the brain is a major contributor to the cellular pathology and cognitive impairment observed in Alzheimer’s disease (AD). In part, Aβ exerts its toxic effects by increasing reactive oxygen species (ROS) and neuroinflammation in the brain. Aging, a major risk factor for AD is also associated with increased production of ROS. This study investigated the age-related pathological response to Aβ toxicity and examined whether catalase-SKL(CAT-SKL), a genetically engineered derivative of the peroxisomal antioxidant enzyme catalase, is able to reduce Aβ toxicity. Bilateral intracerebroventricular (icv) injections of the Aβ25-35 peptide was used to model Aβ toxicity in 3, 6 and 9 months old male Wistar rats. A subset of 6 months old rats undergoing CAT-SKL treatment received CAT-SKL injections intraperitoneally (ip) once a week for four consecutive weeks. Control animals received bilateral icv injections of the reverse physiologically inactive Aβ35-25 peptide. Spatial learning and reference memory were assessed using the Morris Water Maze (MWM); histopathological and immunohistochemical analyses were used to evaluate neuroinflammation, and neuronal degeneration. Aβ25-35 icv administration in animals 6 and 9 months of age resulted in increased microglia activation and decreased number of cholinergic neurons in the basal forebrain and loss of neuronal integrity in the hippocampus in comparison to Aβ25-35 induced pathology in 3 months old animals. CAT-SKL treatment significantly decreased microglia activation and reduced cholinergic neuronal loss in the basal forebrain. Aβ25-35 animals showed deficits in long-term reference memory in the MWM, which was effectively ameliorated in Aβ25-35 animals treated with CAT-SKL. These findings demonstrate the importance of taking into consideration animal age when modeling Aβ toxicity, and provides support for the use of CAT-SKL in reducing neuroinflammation and long-term reference memory deficits induced by Aβ25-35 in the rat.
Nell, Hayley J., "Investigating the pathological response to beta amyloid toxicity in rats: the role of age and the antioxidant catalase-SKL" (2013). Electronic Thesis and Dissertation Repository. 1497.