Alzheimer's disease (AD) is the most commonly found neurodegenerative disorder in the elderly population. Although the incidence of this devastating disorder continues to increase thus creating a serious public health problem, to date this disorder is neither curable nor preventable. For the current project, we propose a new approach for this modeling and treatment of AD based on the use of lentiviral vectors expressing proteins that enhance or decrease accumulation of products of amyloid precursor protein (APP) metabolism and tau. We postulate that injection of lentiviral vectors expressing mutant presenilin 1 (PS1) or tau into hAPP tg mice will help develop more comprehensive models of AD, while lentiviruses expressing amyloid degrading enzymes as neprilysin (Nep) or insulin degrading enzyme (IDE) could be used as targets for the development of an alternative treatment for AD. In this context, we propose the following Specific Aims: 1. To determine the potential use of recombinant lentiviral vectors expressing mutant PS1 or APP in developing tg models of amyloid deposition in the brain. The hypothesis is that lentiviral vectors expressing pro-amyloidogenic vectors will accelerate plaque formation in a time- and region-specific manner. 2. To determine the potential therapeutic use of recombinant lentiviral vectors expressing Nep or IDE to reduce amyloid in the brain of tg models. The hypothesis is that injection of lentiviral vectors expressing Nep or IDE will reduce the amyloid burden in the brains of hAPP tg mice and that this will result in improved functional performance and reduced neurodegeneration. 3. To determine the potential use of recombinant lentiviral vectors expressing mutant tau in developing new tg models of AD. The hypothesis is that injection of lentiviral vectors expressing mutant tau into the brains of hAPP tg mice will result in formation of neurofibrillary tangles (NFTs) in a time- and region-specific manner. For all these aims, tg mice will receive lentiviral injections either in the frontal cortex, hippocampus, or cerebellum. Mice will undergo detailed neurochemical and neuropathological analysis to assess the regional specificity and potential for formation of amyloid and NFTs by the lentiviral constructs. Taken together these studies will help develop new treatments for AD based on the use of anti-amyloidogenic viral vectors.
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