IMMUNE-MEDIATED MECHANISMS UNDERLAYING CNS AB CLEARANCE
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DESCRIPTION (From the applicant's abstract): Abeta 1-42 immunization of PDAPP transgenic mice before or after deposition of Abeta as amyloid stimulates the production of high titer anti-Abeta antibodies and decreases age associated Abeta deposition and other AD-like pathology (1). These novel observations indicate that activation of the immune system by Abeta immunization can increase clearance of Abeta in this transgenic mouse model. If similar phenomena can be induced by immunization of human subjects at risk for AD or in the early stages of AD, then it is possible that Abeta immunization could be a viable therapeutic strategy to prevent or even treat AD. In order to better evaluate the therapeutic potential of Abeta immunization it will be necessary to i) determine if this is a reproducible phenomena or is restricted to the PDAPP mouse model; ii) characterize the mechanism through which Abeta immunization results in increased Abeta clearance; iii) identify whether immune tolerance is likely to inhibit an anti- Abeta immune response in humans and; iv) evaluate whether Abeta immunization has the potential to induce autoimmune responses. Therefore, we propose to: Evaluate the effects of Abeta 1-42 immunization on Abeta deposition in the Tg2576 mouse model. Determine the effect of Abeta immunizations on Abeta clearance in Tg2576 mice that have been crossed with Fc receptor knockout mice and B-cell deficient mice. Evaluate the immunogenicity of human Abeta in the guinea pig, an animal who's Abeta sequence is identical to human sequence and if immune activation can be documented, screen the immunized guinea pigs for clinical and pathological signs of autoreactivity.
