NEW FORMULATION OF LITHIUM IMPROVES COGNITIVE PERFORMANCE IN EARLY STAGES OF ALZHEIMER-LIKE AMYLOID PATHOLOGY IN TRANSGENIC RATS

Abstract

Background: Aging in the immune system results in tendency to proinflammatory responses. DNA immunization shows a Th2 polarized non-inflammatory immune response, but with reduced levels of plasma antibodies. Findings presented here are significant as the patient population for potential Ab42 immunotherapy is the elderly in which the immune system shows changes due to immunsenescence. Methods: 18 month old B6SJL mice were immunized with Ab42 peptide, DNA Ab42 trimer or two different prime boost protocols identical to previous experiments.*.Antibody levels and isotypes were determined from plasma. ELISPOTand ELISAs for IFNg, IL-17, IL-10 were used to determine cytokine production in re-stimulated cell cultures. T cell proliferation was measured by CFSE dilution and IFNg producing cells were identified by intracellular flow cytometry. Results: High Ab42 antibody levels were found in 18 month old mice which had received six peptide immunizations (1,070 mg/ml plasma), and in mice which had received peptide prime/DNA boost immunizations (670 mg/ml), compared to antibodies in DNA Ab42 immunized mice with 120 mg/ml. No T cell proliferation and cytokines were found in DNA immunized mice. Different from results in adult mice*, we found T cell proliferation and high levels of inflammatory cytokines in mice which had received DNA boost immunizations, Up to 680 pg IL-17/ml or 13,000 pg/ml IFNg were found in Ab42 re-stimulated cultures from these mice compared to 40 pg/ml or 1,500 pg/ml in the DNA immunized mice. ELIPOTanalyses showed confluent cell layers secreting IL-17 or IFNg after Ab42 peptide re-stimulation (>1000 spots/10 6 cells) in peptide immunized mice and the two prime boost groups compared to 1068 IFNg spots or 261 IL-17 spots in DNA immunized mice. IFNg was produced mainly by CD8+ T cells as measured by intracellular staining after 72h in cell culture. Conclusions: The results are in concordance that immunsenescence in general leads to pro-inflammatory immune responses and contraindicate the use of Ab42 peptide immunizations as well as a prime boost immunization protocols for the use in elderly AD patients. DNA Ab42 immunization only on the other hand does lead to high levels of antibodies without inflammatory cytokine or T cell responses in the aged animal model tested. *Lambracht-Washington et al. 2013, Journal of Neuroimmunology.