All ETDs from UAB

Advisory Committee Chair

Erik D Roberson

Advisory Committee Members

Lawrence J Delucas

Farah Lubin

David G Standaert

Scott Wilson

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disease and with Americans’ increasing longevity it is becoming an epidemic. There are currently no effective treatments for this disorder. Abnormalities of tau track more closely with cognitive decline than the most studied therapeutic target in AD, amyloid-beta, but the optimal strategy for targeting tau has not yet been identified. Based on considerable preclinical data from AD models, we hypothesize that interactions between tau and SH3 domain–containing proteins are pathogenic in AD. Genetically reducing either tau or tau interactants has beneficial effects relevant to AD. Here, we describe a drug screen for inhibitors of the interaction between tau and the SH3 domain–containing protein Fyn which is likely to provide leads for inhibition of other tau-SH3 interactions as well. Furthermore, we describe previously unknown roles of two of the leading genetic risk factors for AD uncovered during investigation of their potential role as tau interacting proteins, including CD2 associated protein (CD2AP) and BIN1. We identified a role for CD2AP in maintaining blood-brain barrier integrity, a role that may or may not involve tau. Furthermore, we identified a role for the tau interactant BIN1 in mediating excitability through a voltage gated calcium channel and calcium activated potassium channel complex, which provides new insight into potential therapeutic avenues for AD.

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