This proposal seeks to develop a collaboration between the PI and Dr. Goni and Dr. Chabalgoity at the University of Uruguay. The Pi's laboratory is developing a novel immunization approach which is non-toxic for the treatment of Alzheimer's disease (AD) related amyloid in model mice, as well as vaccination to treat prion diseases. A major problem with vaccination approaches for these disorders in humans is potential toxicity. Both Dr. Goni and Chabalgoity are Immunologists, with Dr. Chabalgoity having a long experience with the development of various vaccines. The toxicity noted with the AD vaccine in humans has been linked to excessive cell mediated immunity, resulting in encephalitis in a about 6% of patients, whereas the beneficial amyloid clearing effects have been associated with humoral immunity. One way of inducing primarily a humoral, antibody mediated immune response is to induce mucosal immunity. We propose: 1. To develop mucosal active immunization for use in Alzheimer transgenic model mice using Salmonella vaccine strains, with the aim of inducing primarily a humoral immune response which will not be associated with toxicity. These will be used in conjunction with our Aft homologous peptides, which are non fibrillogenic and non-toxic. 2. Behavioral studies will be done and the amyloid burden will be determined in vaccinated and control AD model mice. The presence of any hemorrhages will be assessed. These histological measurements will be correlated with Ali peptide brain levels both in the soluble and insoluble fractions. 3. In the AD model animals the Th-1 versus Th-2 response will be monitored by the profile and magnitude of cytokine production as well as specific antibody titers in the Gl tract and systemically. In order to characterize the kind of humoral immune response generated, monoclonal antibodies will be produced using lymphocytes extracted from the Peyer's patches and spleens of mice with a positive outcome. This proposal will greatly enhance capacity building at the University of Uruguay with the transfer of AD transgenic model expertise and monoclonal antibody production capability. In addition it will produce preliminary data for the development of potentially non-toxic vaccination approaches for the treatment of AD. Lay Summary: AD is the most common cause of dementia. Vaccination is potentially an effective treatment, but is associated with significant toxicity in about 6% of patients. We propose studies to help develop safe, effective vaccines. ? ? ?
| Boutajangout, Allal; Goni, Fernando; Knudsen, Elin et al. (2009) Diminished amyloid-beta burden in Tg2576 mice following a prophylactic oral immunization with a salmonella-based amyloid-beta derivative vaccine. J Alzheimers Dis 18:961-72 |
| Goni, F; Prelli, F; Schreiber, F et al. (2008) High titers of mucosal and systemic anti-PrP antibodies abrogate oral prion infection in mucosal-vaccinated mice. Neuroscience 153:679-86 |
