Proinflammatory Cytokine Overproduction: A Contributor to Pathophysiology

New Alzheimer's disease (AD) drugs that alter disease progression are urgently needed. The long term goal of our research is to test the hypothesis that safe and effective, disease-modifying drugs for AD can be developed by targeting the overproduction of molecules from glial cells, the cells in the brain that produce inflammation responses. Glial cells normally cooperate with the nerve cells to keep the brain operating smoothly. When an injury or change in the brain occurs, the glial cells mount a beneficial inflammation response to fight off the insult and restore the brain to its proper functioning. While a controlled inflammatory response is an important element in protecting the brain, this beneficial process sometimes gets out of balance and the inflammation becomes too strong or does not shut off on schedule. In AD, glial cells are over-activated and produce detrimental inflammatory molecules called proinflammatory cytokines that can contribute to nerve cell death and accelerate the progression of the disease. This raises the logical question of whether drl!gs can be developed to selectively target cytokine up-regulation in glia, with the hope that such drugs would slow down or perhaps even prevent disease progression. We have recently developed a novel experimental therapeutic, called compound 069A, that is safe and effective in animal disease models, readily enters the brain, and is able to be taken by mouth. In a mouse model of AD, compound 069A suppresses the overproduction of proinflammatory cytokines in the brain back towards normal levels, which prevents subsequent nerve cell damage and cognitive deficits. Compound 069A is an inhibitor of a key enzyme, called p38 mitogen activated protein kinase (MAPK), that controls the production of proinflammatory cytokines. The p38 MAPK family, especially p38alpha, is an established therapeutic target for peripheral inflammatory disorders such as rheumatoid arthritis. However, much less is known about the potential in vivo involvement of p38alpha, or the closely related p38beta isoform, in the increased production of brain proinflammatory cytokines. This project will test the hypothesis that p38alpha is a key in v;vo contributor to increased brain proinflammatory cytokine production and neuronal dysfunction in response to stressors, and is a viable CNS drug discovery target for disorders characterized by increased proinflammatory cytokine production as part of pathology progression. To test this hypothesis, we will employ a combination of unique mouse models and our novel small molecule compound. Successful completion of this project will provide mechanistic insight into how the key regulatory protein p38alpha MAPK is involved in AD-relevant pathophysiology progression, and will provide immediate impetus for further development of p38alpha-targeted compounds into future, potentially disease-modifying drugs for AD.