| Plaques and other aggregates of beta-amyloid (Abeta) are hypothesized to cause human Alzheimer's disease (AD). I have studied two natural non-human models that exhibit Abeta deposition. Extensive Abeta plaques appear invariably in spawning kokanee salmon (Oncorhynchus nerka kenneryli) and occasionally in a few other species, but not rodents, or other common research animals. I explored physiological and biochemical explanations for why kokanee aggregate Abeta, anticipating that the results would be broadly relevant to humans and other species. I also explored a life-history explanation for Abeta aggregation by examining a marsupial mouse, Antechinus stuartii, with similarities to the salmon model and potential for use in AD research.; Initially, I investigated a neurotoxic and Abeta-promoting role for cortisol, a stress hormone elevated in AD and in spawning kokanee. Cortisol treatment produced spawning cortisol levels in hatchery-reared kokanee, without obvious changes in neurodegeneration, or Abeta aggregation. Hatchery-reared kokanee, but not wild kokanee, demonstrate intraneuritic P3, a benign, shorter version of Abeta that is cleaved from Abeta-precursor protein (APP). Intraneuritic P3 was less apparent in vehicle-treated kokanee with elevated endogenous plasma cortisol. A possible interaction between the hypothalamo-pituitary-interrenal axis and APP processing is suggested.; Among the many Abeta variants produced within and across species, Abeta 42 is exceptionally aggregation-prone and implicated in AD. Sequencing and mass spectrometry revealed abundant Abeta42 in spawning kokanee brains, but no Abeta40, which inhibits Abeta42 aggregation. Furthermore, this biochemical "recipe" for aggregation may be encoded by a sequence similarity between kokanee's PS1 gene and a PS1 mutation that causes familial AD and an elevated ratio of Abeta42 to total Abeta.; In collaboration with Dr. Bronwyn McAllan at The University of Sydney, Australia, I investigated a correlation between a semelparous life-history and Abeta aggregation. In contrast to kokanee, only male A. stuartii are semelparous. Because both male and female A. stuartii exhibited sparse Abeta plaques, semelparity is not universally associated with extensive Abeta aggregation.; In kokanee, humans, and A. stuartii, the mechanism of Abeta aggregation remains incompletely solved. However, biochemical data strengthened the relevancy of research on kokanee to humans and provided insight into why kokanee aggregate Abeta. Stress and cortisol may yet be shown to influence APP processing in humans, kokanee and A. stuartii. Overall, studies in these 3 species may complement each other and enhance our understanding of Abeta aggregation and AD. |
