Functional Consequences of Vaccination in AD Tg Mice

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Amyloid is a major pathological feature of Alzheimer's disease and a target of many therapeutic agents currently under development. In the first years of this grant we found that immunotherapyagainst the amyloidogenic ABpeptide, was remarkably effective in mouse models of amyloid deposition. Subsequent human clinical trials of active immunizationagainst the AJ3 peptide were suspended due to adverse events in a subset of patients. However, in at least one cohort of patients, individualsdeveloping antibodies which react with brain plaques benefited with cognitive stabilization. An alternative to vaccines, passive immunization has the advantages of controlled dosing and the ability to terminate immunotherapyif adverse reactions become manifest. Moreover, T-cell involvement, argued to be the basis for the adverse events in the suspended clinical trial, should not be present with adoptive transfer of antibody approaches. Preliminary data reported here with passive immunotherapy of old transgenic mice shows remarkable reversal of cognitive deficits and dramatic reductions in diffuse and fibrillar plaques. However, there were also increases in vascular amyloid deposits and a few sites containing extravascular hemoglobin. This competing continuation will seek passive immunization conditions which maximizethe cognitive benefits and reductions in parenchymal amyloid load while minimizingthe potentially deleterious vascular damage or other adverse consequences. This application will test passive immunotherapyin 3 aims. The first aim will evaluate the effects of age, amyloid load, and speed of amyloid removal on these processes. The second aim will compare antibodies with different epitopic specificities and measure the efficacy of different antibody fragments. In aim 3, alternative mechanisms will be investigated by examining mice with a preponderance of vascular deposits, the effects of corticosteroid suppression of microglia activation and the use of antibodies with strictly peripheral distribution . Success in these aims will identify conditions of passiveimmunization which maximizethe cognitive benefitswhile retaining high levels of patient safety for clinical trials in patients with Alzheimer's disease.