Attenuating Proinflammatory Cytokine up-Regulation as an AD Therapeutic Strategy

The hypothesis to be tested in this project is that orally delivered drugs that inhibit the immune response by activated glia can reduce Alzheimer’s related neurodegeneration.

New Alzheimer’s disease (AD) drugs that alter disease progression are urgently needed. The long term goal of our research is to develop safe and effective drugs for AD by targeting the overproduction of inflammatory molecules from glial cells, the cells in the brain that produce detrimental 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 drugs 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. In our Center for Drug Discovery and Chemical Biology, we are using a drug discovery platform that integrates what we call ‘smart chemistry’ with ‘smart biology’ to develop new small molecule compounds that selectively suppress the overproduction of proinflammatory cytokines in the brain. We have developed two exciting new drug-like compounds, named Minozac and Minokine, that are safe in animals, readily enter the brain, and are able to be taken by mouth. We have found that these compounds suppress the glial cytokine production back towards normal levels, which prevents subsequent nerve cell damage and learning deficits in an animal model of early stage AD. Our proposed project will extend these findings to test Minozac and Minokine for effectiveness in a more severely affected AD transgenic mouse model, in order to ask whether the compounds are effective not only at preventing or suppressing cytokine-driven neurologic damage in early stages, but are also effective under conditions of increasing disease severity. Successful completion of this project will provide immediate impetus for further development of these compounds into future, potentially disease-modifying drugs for AD.