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Evidence that inhibition of gamma-secretase impairs axonal and dendritic structure and function: a necessary role for APP


Due to their impact on amyloid precursor protein (APP) processing, gamma secretase inhibitors (GSIs) have recently been considered for treatment of Alzheimer's disease. Recent evidence now indicates that inhibition of gamma-secretase results in cognitive impairment and neuronal dysfunction; however, a mechanism by which this occurs remains elusive. The two most well studied substrates of gamma-secretase, APP and Notch, are proposed to play essential roles in neuronal toxicity experienced, but a direct report of their effects has yet to be performed. Importantly, the role that increased APP CTFs, which GSI treatment directly produces, is only beginning to be understood in terms of neuronal dysfunction. Therefore, the main body of this dissertation will address the impact that GSI treatment has on wild-type neuronal function as it pertains to the substrate APP. The main output of neuronal function assessed was axonal trafficking and signaling of brain-derived neurotrophic factor (BDNF), a critical neurotrophic factor involved in the maintenance of synaptic connections in the adult central nervous system.

In brief, Chapter 1 of this dissertation will provide an overview of neurotrophic factors and expand their application to include treatment of disorders using neurotrophic factors. Chapter 2 will provide a direct look at APP and APP processing by highlighting unique transport characteristics of various APP and APP CTF positive vesicles. Chapter 3 will bring both APP and neurotrophic factors together in a study of GSI treatment on wild-type neuronal function with an emphasis on BDNF trafficking and signaling mechanisms.

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