Graduation Year

2006

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Biology

Major Professor

Gary Arendash, Ph.D.

Keywords

Active vaccination, Fish oil, DHA, Cognitive performance, Plaque deposition

Abstract

Major therapeutics against Alzheimer's disease (AD) are targeted towards reducing beta-amyloid in the brain and improving cognitive performance. Transgenic mouse models of AD have become critical in the development of such therapeutics to protect against or treat AD. This dissertation examined the potential protective effects of both active A-beta immunotherapy and dietary omega-3 fatty acid administration to AD transgenic mice. First, immunization with A-beta 1-42 from 2-16 1/2 months of age provided protection against cognitive impairment in APP/PS1 transgenic mice well into older age. At both adult (4 1/2-6 month) and aged (15-16 1/2 month) test points, an extensive 6-week behavioral battery was administered that measured multiple sensorimotor and cognitive domains. A-beta immunotherapy either partially or completely protected APP/PS1 mice from impairment in reference learning/memory, working memory and/or recognition/identification at these test points. However,

behavioral protection at the later test point occurred without any reduction in A-beta deposition within the brain. Therefore, the cognitive benefits of A-beta immunotherapy most likely involved neutralization or removal of A-beta oligomers from the brain. In addition to immunotherapy, this dissertation also examined the behavioral and neurochemical effects of a high omega-3 (n-3) or high omega-6 fatty acid (n-6) diet to NT and AD transgenic (Tg+) mice from 2 through 9 months of age. The same 6-week behavioral test battery, as described above, was administered between 7 1/2-9 months of age. In NT mice, dietary n-3 or n-6 fatty acids did not result in any beneficial effects on cognitive performance. In Tg+ mice, a high n-3 diet improved some, but not most, cognitive skills in comparison to standard-fed Tg+ mice; whereas a diet high in n-6 fatty acids did not lead to widespread deficits in learning or memory. In fact, there was no difference in overall performance on any behavioral

task between Tg+ mice given a high n-3 or high n-6 diet. Administration of dietary fatty acids did not result in any significant changes in soluble or insoluble A-beta levels within the brains of Tg+ mice and plasma cytokine levels in Tg+ mice were largely unaffected. Notably, neither the high n-3 nor high n-6 diet increased cortical levels of n-3 or n-6 fatty acids, respectively, within Tg+ mice. However, NT mice on a high n-3 or high n-6 diet did show significant elevations in cortical n-3 or n-6 fatty acid levels, respectively, suggesting that Tg+ mice have a deficit in incorporation of dietary fatty acids in the brain. Collectively, these results show that life-long administration of active A-beta immunotherapy provides clear cognitive protection well into older age, whereas long-term dietary omega-3 fatty acid administration does not provide extensive cognitive benefit. Both studies underscore the value of using AD transgenic mice in determining the efficacy of prophylactics

against AD.

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