We are investigating the mechanisms that cause neurodegeneration in Alzheimer’s disease. Our recent studies have led us to realize that a toxic protein is unexpectedly secreted by a class of brain cells called astrocytes in the setting of Alzheimer’s disease. Our goal in this proposal is to identify this protein so that, in future studies, we can test whether drugs that block the production or action of this protein will be useful as new therapies for Alzheimer’s disease.
Together our findings from the first year of this project provide strong evidence that the formation of A1 neurotoxic reactive astrocytes is a fundamental neuropathological response of the mammalian brain to acute injury and neurodegenerative disease that has important implications for the development of new treatments for these diseases. By targeting A1s in order to prevent their formation, revert A1s back to normal astrocytes or to good/reparative A2 reactive astrocytes, or to block this neurotoxin or its receptor, we hope to develop new drugs that help patients with acute central nervous system injuries, and Alzheimer’s disease and other neurodegenerative diseases. Many questions arise about why the brain would ever generate a neurotoxic type of reactive astrocyte, however. One possibility is that these astrocytes evolved to fight off bacterial and viral infections, possibilities we have begun to investigate. Another interesting question is whether this neurotoxin is formed by epithelial cells in non-CNS tissues and participates in other diseases of cell death, for instance, Type 1 diabetes.