Advisory Committee Chair
Erik Roberson
Advisory Committee Members
Rita M Cowell
Jeremy Day
Cristin Gavin
Jeremy Herskowitz
David Standaert
Document Type
Dissertation
Date of Award
2021
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide, and its impact will increase with an aging population. It is characterized by dementia associated with accumulation of extracellular amyloid-β (Aβ) plaques, intracellular hyperphosphorylated Tau tangles, and neurodegeneration. Additionally, network hyperexcitability occurs early in AD and likely contributes to disease pathogenesis. Current therapies provide minor delay of disease progression at best, so it is imperative to develop novel therapeutic approaches to prevent and treat AD. As Tau pathology correlates better with cognitive function than Aβ pathology and Tau reduction prevents Aβ-induced dysfunction in preclinical models, targeting Tau is a growing approach for AD. Here, we provide evidence that Tau’s interactions with SH3 domain–containing proteins permit Aβ toxicity and describe a drug development pipeline harnessing this novel therapeutic target: inhibiting Tau-SH3 interactions. We developed a peptide inhibitor of the prototypical Tau-SH3 interaction in AD, Tau-Fyn, and determined that the inhibitor ameliorates Aβ toxicity in primary neurons. We next describe the role of BIN1, a leading AD genetic risk factor that binds Tau through its SH3 domain, in promoting network hyperexcitability. We found that Tau regulates BIN1-induced network hyperexcitability by forming a complex with BIN1 and SH3 domain– iv containing voltage-gated calcium channels. Finally, we describe a drug development pipeline that identifies a novel hit small molecule Tau-SH3 interaction inhibitor, develop lead compounds, and explore the top lead SR42667. We found that SR42667 ameliorates Aβ-induced metabolic dysfunction, neurite degeneration, and network hyperexcitability in neurons. It binds Tau rather than FynSH3 and is a selective Tau-SH3 inhibitor that does not alter normal Tau function. Together, these data provide evidence that inhibiting Tau-SH3 interactions is a potential novel therapeutic target to prevent Aβ-induced dysfunction and network hyperexcitability in Alzheimer’s disease.
Recommended Citation
Roth, Jonathan, "Tau-SH3 Interactions and Alzheimer's Disease" (2021). All ETDs from UAB. 555.
https://digitalcommons.library.uab.edu/etd-collection/555