Title: Neuroinflammation as a therapeutic avenue for Alzheimer's disease treatment The role of neuroinflammation in neurological disorders remains controversial. While triggered by the toxic accumulation of A?, Alzheimer's disease (AD) is thought to be potentiated by blood-brain barrier (BBB) breakdown and immune cell infiltration to the brain. However, drugs that inhibit immune cell infiltration to the CNS have failed as treatments for AD. In other disease models, like infection with the neurotropic parasite Toxoplasma gondii, neuroinflammation is required for survival of both mice and humans, yet almost all of the infected population (over 2 billion people worldwide) harbors a life-long asymptomatic infection. Thus, T. gondii infection models an immune response that is robust to control the parasite yet tightly controlled prevent immune mediated pathology in the brain. Our lab has discovered that of the three canonical T. gondii strains, infection with type II parasites protects against A? deposition in the brain. Though prolonged inflammation has been shown to promote alternative activation in monocyte lineage cell types, data generated in our lab shows that type II parasites induce a larger population of alternatively activated macrophages in the brain. Therefore, I hypothesize that infection with type II parasites generates a population of phagocytic, alternatively activated macrophages that can more easily access the brain and clear ?-amyloid plaques. To test this hypothesis, I will determine the impact type II infection has on the BBB, A? clearance from the brain and the populations of immune cells that infiltrate the CNS compared to infection with type III parasites. This strategy will allow me to quickly separate changes in the brain that aid specifically in A? clearance from changes that occur during infection in general. Identifying the cell types that are capable of eliminating pathogenic plaques from the brain would lead to new strategies to combat the toxic accumulation A?.
Despite the recognized need to control persistent infection in the brain and even the very recent identification of lymphatic vessels in this immune privileged site, the benefits of an immune response in the brain are still poorly understood and controversial. The goal of this proposal is to understand how the common parasite Toxoplasma gondii manipulates the host immune system to result in the prevention of beta-amyloid plaque deposition in the brain. This novel approach may lead to new strategies to combat the toxic accumulation of beta-amyloid and the treatment or prevention of Alzheimer's disease.