Alzheimer's disease (AD) and inclusion-body myositis (IBM) are the most common degenerative diseases in brain and skeletal muscle, respectively, in people over age 50 years. The etiologies of AD and IBM are not fully understood, and no curative treatment is available for either disease. AD and IBM share a number of common pathologies. For example, patients with AD develop amyloid beta-protein (Abeta) deposits and neurofibrillary tangles mainly composed of paired helical filaments (PHF) in brain, while patients with IBM have Abeta-immunoreactive deposits and PHF in skeletal muscle. Increasing evidence supports the notion that Abeta and its precursor, APP, play important roles in the pathogenesis of AD and IBM. Overexpression of the mutant forms of APP in transgenic mice (Tg2576 mice) using neuron-specific promoters lead to many AD-like pathologies, including Abeta-immunoreactive deposits in brain and cognitive deficits. We have generated a transgenic mouse model (Tg13592 mice) utilizing the cytomegalovirus enhancer/beta-actin promoter to overexpress the signal-peptide plus Abeta-bearingg C-terminus [99-amino-acid carboxyl-terminal fragment of APP (C99)] throughout the complete animal. Interestingly, Tg13592 mice developed pathologies remarkably similar to those in IBM patients, including Abeta deposits in skeletal muscle, thus supporting a pathogenetic mechanism common to AD and IBM. Recently it has been shown that inducing an immune response against Abeta by repeated needle injection or nasal administration of synthetic Abeta prevented or reduced Abeta deposits in such transgenic mice, and improved their behavioral deficits, suggesting that immunization with Abeta might be a therapeutic and preventive option for AD. We propose to use a noninvasive vaccination modality whereby defective adenovirus vectors encoding all or part of Abeta and/or C99 are applied onto the nasal membrane of mice in order to elicit a potent immune response against Abeta and/or C99.
The specific aims are to perform pilot studies in order to choose promising cDNA constructs of Abeta and C99 for therapy, to immunize Tg2576 and Tg13592 transgenic mice by applying adenovirus vectors bearing chosen cDNAs onto nasal membranes, and to evaluate the efficacy of the vaccination in prevention and clearance of Abeta deposits by comparing its efficacy with that of conventional needle injection vaccination using synthetic Abeta. The nasal membrane application procedure eliminates pain and other problems associated with needle injection, protein purification, and adjuvant modification, and so may reduce medical costs.
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