Throughout my undergraduate career I was fascinated with the brain and the mental and physical disorders that were associated with it. I chose to major in psychology because it encompassed my interests and allowed me to explore the brain and related diseases. After interning at a neuropsychological clinic in Grand Rapids, Michigan I found that clinical work was enjoyable, but was not the angle of education my interests lied in. After discussing with my professors I found my interests were rooted in the hard sciences of the brain: biology and chemistry. The next summer I had the opportunity to do research in Dr. Gamblin’s lab at the University of Kansas and my project focused on compounds derived from Aspergillus nidulans as possible chemical scaffolds for Alzheimer’s disease therapeutics. After receiving my B.A. in Psychology from the University of Minnesota Morris I was invited back to the University of Kansas to work in Dr. Gamblin’s lab to pursue my PhD in Neuroscience. My graduate work has been similar to my summer research by continuing to find chemical scaffolds to inhibit tau aggregation, but is more in depth. The current endeavor is characterizing the compound’s mode of action to understand how they are interacting with tau to inhibit aggregation as well as utilizing medicinal chemistry to improve their efficacy.
Tau is a microtubule-associated protein that is mainly expressed in neurons found in the brain where is serves to stabilize the microtubule cytoskeleton required for axonal transport. The aggregation of this protein into fibrils that accumulate in pathological structures such as neurofibrillary tangles is believed to be a direct cause of cellular dysfunction and neuronal death in Alzheimer’s disease (AD) and other related neurodegenerative disorders. AD is a serious health care problem in the US, affecting an estimated one in eight elderly Americans at an annual cost of more than $250 billion. There are no currently approved therapeutic strategies that inhibit or reverse the formation of pathological structures in AD, and identifying aggregation inhibitors is therefore a significant area of research. We are exploring the possibility that natural products could be identified as tau aggregation inhibitors due to the large number of natural products that have been developed into useful drugs. Although fungal secondary metabolites have been an extremely important source of natural products for drug development, their production, purification and identification have been difficult due to their scarcity under normal laboratory conditions. Dr. Berl Oakley (KU) and Dr. C.C. Wang (USC) have overcome this barrier by genetically engineering the fungi Aspergillus nidulans to overproduce a wide variety of secondary metabolites. Using an in vitro tau aggregation protocol utilizing arachidonic acid, we have identified several potential tau aggregation inhibitors, and a subset of these have the advantageous property of disassembling pre-formed aggregates. We are now in the process of further characterizing the efficacy and mechanism of inhibition for these compounds. We conclude that this library of A. nidulans secondary metabolites is a rich source for lead compounds with tau aggregation inhibition activity for further development into potential therapeutics for AD and related neurodegenerative disorders.