Erin E. Congdon, PhD

Much of my research has focused on tau assembly, both understanding the mechanism through which it occurs and investigating compounds which affect tau polymerization and clearance. While in the Kuret lab we identified beta sheet binding dyes as a novel tau aggregation promoters, allowing us to stimulate polymerization in full length tau at much lower concentrations than was previously possible. Utilizing these inducers and biophysical methods we were able to identify key steps in the polymerization pathway and estimate the elementary rate constants associated with each step. In addition, we identified cyanine dyes as an inhibitor of tau polymerization in recombinant protein. Expanding on these results it was shown that cyanines display a complex dose response effect on tau with low concentrations of the compound inhibiting tau assembly and higher doses promoting it.  

This research continued during my post-doctoral training in the Duff lab utilizing organotypic cultures produced from animal models of tauopathy. We were able to recapitulate the biphasic response in two different transgenic lines. Interestingly, in culture the response curve is shifted with tau inhibition occurring at nanomolar concentrations. In addition, I have worked on projects involving the use of autophagy modulating compounds on tau pathology. This work identified methylene blue as an mTOR inhibitor, a novel mechanism of action, and also demonstrated that gender influenced its efficacy in preventing and rescuing cognitive decline in mice.

At NYU, my work has focused on the mechanism of uptake of anti-tau antibodies and the efficacy of those antibodies in reducing tau pathology. We have found that tau antibodies readily enter neurons and that extent of tau pathology correlates strongly with this uptake. Additionally, using pharmacological inhibitors of endocytosis we have shown that the majority of this uptake occurs via clathrin dependent receptor mediated endocytosis. Further experiments revealed that the majority of uptake is via FcgII/III low affinity receptors. Additionally, we have shown that antibodies can clear tau both extra- and intracellularly depending on the experimental design. 

The role of autophagy in neurodegenerative disease has remained of interest, and will become a major focus of my research as an independent investigator, and specifically the role of microautophagy. The reciprocal relationship between tau pathology and this pathway has not been well studied, but is potentially important in the development of neuronal dysfunction in disease.