Vaccination is the only prophylactic or therapeutic intervention that has ever eliminated a disease (e.g. smallpox). It also has well established utility in disease therapy (e.g. rabies). Transgenic mouse models of Alzheimer's disease (AD) develop high density A-beta deposits in cerebral cortex and hippocampus, neuritic changes and, ultimately, inflammatory reactions to these deposits. Recently, vaccination of the PDAPP transgenic mouse with A-beta peptide was found to prevent A-beta deposition in the brain. Unfortunately, the functional consequences of this treatment could not be effectively assessed in these mice, owing to severe learning and memory deficiencies observed early in the lifespan. The investigators propose to assess the functional consequences of vaccination in their doubly transgenic mAPP/mPS1 -mouse model of AD. These mice develop learning and memory deficits which correlate with the accumulation of A-beta, deposits. They will test whether vaccines that prevents/reduces A-beta accumulation can either attenuate or aggravate the behavioral deficits found in these mice. They predict different outcomes depending on the age of vaccination. They will verify histopathologically and biochemically that the vaccines reduce A-beta loads in the CNS, while carefully documenting the degree of inflammation found in these mice. In addition to testing the vaccination hypothesis, these data will address the question of A-beta amyloid's role in cognitive dysfunction. Anticipating that prophylactic vaccination at early ages will ameliorate some of the behavioral deficits normally occurring in these mice, they'll investigate alternatives to the A-beta1-42 peptide as vaccines, and test their effectiveness in old as well as young mice. One less expensive alterative to peptides are DNA vaccines, a novel inoculation technique which elicits both humoral and cellular immunity. This technology is already in human clinical trials. Passive immunization with polyclonal and monoclonal antibody preparations is an alterative to vaccines that will be tested for efficacy in this animal model. Advantages of passive immunization are safety and potentially greater effectiveness in older individuals with poor immunization responses to vaccines. Together, these later studies will determine the relative contributions of humoral and cellular immune reactions in mediating the effects of vaccines in transgenic mouse models of AD.
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