The Role of the Kynurenine Pathway in Microglia in Alzheimer's Disease
MentorPaul Muchowski, Ph.D. J. David Gladstone Institutes
The major goal of this proposal is to use genetic and pharmacological approaches in mouse models of Alzheimer's disease to characterize the contribution of the microglial kynurenine pathway to the pathogenesis of AD which may potentially contribute to the current understanding of pathogenesis of AD and provide new treatments.
Microglia are specialized brain cells that support the health and function of neurons. In response to brain injuries, these cells produce a large number of molecules that participate in inflammation and wound repair. While acute glial responses may help prevent neuronal damage, prolonged or aberrant activation of these cells may contribute to neurological disease. I am using genetic and pharmacological strategies to assess whether glial cells and their products contribute to cerebral amyloidosis and neurodegeneration in Alzheimer's disease. Researchers have previously found that a certain microglial enzyme that is active in the metabolism of tryptophane (an amino acid) might be responsible for the production of neurotoxic substances. In AD patients this enzyme might be more active than usual. However, the inactivation of this enzyme by drugs might help to prevent the progression of AD pathology. The proposed experiments will increase our understanding of the role of microglia in Alzheimer's disease and may also provide information critical for the preclinical development of drugs for Alzheimer's disease.