Title: Transgenic mice expressing individual Abeta peptides. Transgenic mouse models have been developed that deposit Abeta in the brain. However, to generate sufficient Abeta to cause amyloid deposition current models overexpress human mutant APP at levels at least 3-5 fold greater than endogenous mouse APP. Thus, any study of the role of Abeta deposition in AD using current transgenic mice is potentially confounded by overexpression of APP. At present there are no animal models that generate Abeta in the secretory pathway, in the absence of APP overexpression, at levels sufficient to cause amyloid pathology. This is significant because accumulation and deposition of Abeta, in AD, occurs in the absence of APP overexpression. To develop a system where individual Abeta peptides are efficiently expressed and secreted without APP overexpression, we created transgenic mice that express BRI-Abeta, fusion proteins. The fusion is between the BRI protein involved in amyloid deposition in Familial British Dementia and Abeta1- 40/42. Initial characterization of mice that express either BRI-Abeta1-40 or BRI-Abeta1-42 indicate that Abeta40 or Abeta42 levels are elevated, respectively, to levels equivalent to APP695NL (Tg2576) mice. In this proposal, we will test the hypothesis that overproduction of secreted Abeta will induce similar amyloid deposition to mutant APP mice and that, in the absence of sAPP overexpression, this will recapitulate more fully the pathology seen in AD. In addition, by comparing mice that generate Abeta40 and Abeta42 alone with bigenic mice expressing both Abeta40 and Abeta42 we will examine the role of individual Abeta peptides in development of amyloid pathology.
The specific aims are: (1). To characterize BRI-AIbeta42 and BRI-Abeta40 mice and determine the time course of Abeta accumulation and associated pathology; (2). To examine the respective roles of Abeta40 and Abeta42 in seeding Abeta deposition, plaque growth and other pathology by examining the temporal course of Abeta deposition in bigenic mice from the following crosses a) BRI-Abeta40 X BRI-Abeta42 mice; b) BRI-Abeta40 X APP695 wt (Tg5649) and APP695 NL (Tg2576) mice; c) BRI-Abeta42 X APP695 wt and APP695 NL mice. (3). To assess whether behavioral alterations occur in BRI-Abeta40 and BRI-Abeta42 mice and determine the relationship of any observed behavioral alterations with the pathological changes observed.
