Alzheimer?s disease, the most common neurodegenerative disease associated with aging, afflicts approximately 5 million people in the US, costing well over 200 billion dollars annual. Genetic, pathologic, and limited treatment data suggest that age-associated increases in beta-amyloid (A?) peptides, which aggregate and form deposits, play an important role in initiating and potentiating the disease process. This so-called amyloid hypothesis has led to a major focus on understanding A? dynamics and offered important insights for developing AD therapies. However, to ensure the development of a robust battery of A? therapies, novel approaches to understanding A? dynamics must also be taken. In three different human amyloid precursor protein (hAPP) mouse models, we and others have shown that infection with the neurotropic parasite Toxoplasma gondii decreases A? deposition by > 60%. How T.gondii infection protects against A? remains unknown. The goal of this grant, therefore, is to use T.gondii infection as a model to identify infection-mediated CNS changes that decrease A? deposition. T.gondii is a ubiquitous intracellular parasite that naturally establishes a life-long, asymptomatic CNS infection in both humans and rodents, suggesting that T.gondii and the mammalian CNS have co-evolved. This co-evolution provides a unique tool to find A?-altering CNS pathways that would not be discoverable by other mechanisms. Given the broad range of cellular and immune cell changes in a chronically infected brain, we hypothesize that T.gondii?s protection against A? is multi- factorial and will involve both changes in cellular production and processing of A? and increased A? clearance by innate immune cells (e.g. persistent infiltration of highly phagocytic macrophages). To test this hypothesis, we will leverage our novel finding that of the three genetically-distinct, canonical strain-types (type I, type II, and type III), only infection with a type II strain protects against A? deposition. By comparing CNS changes provoked by protective (type II) and non-protective (type III) T.gondii strains, we can hone in on the changes linked to protection rather than those associated strictly with infection. Using this comparative analysis, we will identify type II-only changes in the canonical pathways involved in production, cleavage and processing, and degradation of A? (Aim 1).
In Aim 2, we will determine how type II infection changes innate immune cell infiltration, polarization, and phagocytosis to protect against A? deposition. The successful completion of these aims will determined if the A?-protective effect of type II T.gondii is driven by changes in APP/A? processing or by changes in CNS innate immune cells or both. These findings will form the foundation for future long-term, mechanistic studies to understand the upstream pathways that lead to the remarkable A? protection provoked by type II infection. Harnessing the T.gondii-CNS interaction will lead to new insights into disrupting A? pathways, offering new highly-needed therapeutic targets.
Alzheimer?s disease (AD) is the most common neurodegenerative disease associated with aging, and beta-amyloid (A?) peptide generation, aggregation, and deposition play an important role in initiating and potentiating the disease process. While there has been recent limited success with an antibody against A?, a fuller arsenal of A? therapies is still required. The goal of this proposal is to fill this gap by taking the novel approach of harnessing the co-evolution between the mammalian brain and the braintropic parasite Toxoplasma gondii, which 3 groups have shown to be protective against A? deposition in 3 different models of AD.
