Graduation Year
2018
Document Type
Dissertation
Degree
Ph.D.
Degree Name
Doctor of Philosophy (Ph.D.)
Degree Granting Department
Medical Sciences
Major Professor
Thomas Taylor-Clark, Ph.D.
Co-Major Professor
Laura Blair, Ph.D.
Committee Member
Danielle Gulick, Ph.D.
Committee Member
Daniel Lee, Ph.D.
Committee Member
Lynn Wecker, Ph.D.
Keywords
Aha1, Alzheimer's disease, chaperones, Hsp90, tauopathies
Abstract
The microtubule associated protein, tau, is involved in regulating microtubule stability and axonal transport. When tau becomes hyperphosphorylated it can disassociate from the microtubules and start to aggregate. These tau aggregates are the hallmarks of many diseases known as tauopathies. The heat shock protein 90 kDa (Hsp90) chaperone network is highly involved in modulating client proteins, including tau. However, during aging and disease the Hsp90 chaperone network becomes highly imbalanced with some Hsp90/co-chaperone complexes increasing, while others are repressed. This imbalance in Hsp90/co-chaperone complexes could result in a worsening of tau pathology in Alzheimer’s disease.
Hsp90 inhibition has been of interest as a potential therapeutic for tauopathies for many years. However, issues with toxicity and bioavailability have dampened enthusiasm for Hsp90 as a viable therapeutic target. Hsp90 co-chaperones are currently being investigated for as potential therapeutic targets for tauopathies, with the hope that targeting co-chaperones will lead to more specific targeting without toxicity. One co-chaperone that has the potential to become a therapeutic target for tauopathies is the activator of Hsp90 ATPase homolog 1 (Aha1).
Aha1 is the only known stimulator of the ATPase of Hsp90, so targeting this particular co-chaperone could potentially mimic the effects of Hsp90 inhibition with more specificity. In this study we found that Aha1 enhanced Hsp90-mediated tau aggregation and increased insoluble tau accumulation in vitro. Additionally, a novel Aha1 inhibitor was able to reduce the formation of insoluble tau in vitro. We also investigated the effects of Aha1 overexpression in the rTg4510 mouse model, which is a tauopathy model that stably overexpresses the P301L mutation of tau. Overexpression of Aha1 in these mice increased the accumulation of insoluble and oligomeric tau. Furthermore, Aha1 overexpression led to cognitive deficits and neurotoxicity. Due to the effect of Aha1 overexpression on tau we wanted to investigate the effects of Aha1 knock-down in the rTg4510 mice. Incredibly, Aha1 knock-down led to reductions in pathological Gallyas silver positive tau tangles and was able to rescue neuronal loss. Overall, this work highlights Aha1 as an important regulator of tau pathology through Hsp90. The Hsp90/Aha1 complex could provide a novel therapeutic target for the treatment of tauopathies.
Scholar Commons Citation
Shelton, Lindsey Brooke, "Targeting the Hsp90/Aha1 Complex for the Treatment of Tauopathies" (2018). USF Tampa Graduate Theses and Dissertations.
https://digitalcommons.usf.edu/etd/7643
