Anti-ABeta Immunity Against Alzheimer's Disease

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DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disease characterized by overproduction of Abeta-amyloid from amyloid precursor protein (APP), with the subsequent pathologic deposition of Abeta into extracellular plaques in regions of the brain which are important for memory. Recently we, as well as others, have demonstrated that vaccination of a transgenic (Tg) mouse which expresses mutant presenilin-1 and APP (and serves as a model for AD) with an Abeta(1-42) peptide, resulted in amelioration of neural pathology and protection of these mice from functional memory deficits. Others have indicated that humoral immunity plays a major role in at least ameliorating the neural pathology. However, the exact role of cellular immunity, whether beneficial or deleterious, has not been addressed. We have recently demonstrated that vaccination of Tg mice with Abeta results in the induction of antibodies indicative of a T helper 2 response. We have also shown strong T cell proliferative activity in mice vaccinated with Abeta stimulated with specific antigen. A chimeric mouse line has recently been developed which expresses human MHC I and II molecules and is called CHAD (chimeric human A2DR). We propose to use this mouse to cross mate with the doubly transgenic mice described above to ask important questions about human immune responses to Abeta. The specific aims of this proposal are as follows: (a) evaluation of the CD4 T cell responses to Abeta in a Tg mouse model for AD; (b) evaluation of the potential role of CD4 T cell responses after Abeta vaccination; (c) evaluation of the CD8 T cell responses in Tg mouse models; and (d) engineering of specific immune responses in AD Tg mice. These studies will comprehensively address the potential role of cellular immune responses to Abeta vaccines.