Jun Tan, Ph.D.

Role of Th1/Th2 Cytokine Modulation in AD-Like Pathology

We propose to establish a strong, well-integrated research program concentrated on the understanding of the role of T helper type 1 (Thl) and T helper type 2 (Th2) cellular immunity in Alzheimer's disease (AD) pathogenesis. It is becoming increasingly clear that Abeta induced immunity responses play an important role in plaque formation in transgenic mouse models of AD. The recently reported immunization of mice with Abeta 42 peptide resulted in decreased Thl and increased Th2 cytokine responses. The modified levels of these cytokines are associated with a dramatic reduction in Abeta amyloid deposition. In addition, independently of the Abeta immunization, modulation of Thl/Th2 immunity responses by blockage of the Thl promoting pathway (CD40-CD40 ligand interaction) attenuates AD-like pathology in the same models.

In accordance with these findings, we hypothesize that modulation of Thl/Th2 associated cytokines peripherally and in the CNS will impact AD-like pathology, particularly, glia-associated chronic inflammation and Abeta plaque formation. To evaluate this hypothesis, we propose to fully characterize the cytokine changes in the periphery and in the CNS of AD mouse models and correlate the observed changes with the reduction of AD-like pathology during Abeta immunization. We wish to examine whether alteration of Thl and Th2 associated cytokines via administration of Th2 cytokines to a transgenic mouse model could modulate AD-like pathology. These studies will provide insight into the mechanism(s) of action of Abeta immunization that leads to mitigation of AD-like pathology. In addition they will highlight therapeutic strategies to boost or enhance the effect of Abeta immunization and allow the development of novel therapeutic strategies for treatment of AD.