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Dissertation
TrkB isoforms differentially modulate amyloid precursor protein metabolism
Doctor of Philosophy (Ph.D.), Drexel University
Nov 2010
DOI:
https://doi.org/10.17918/etd-3412
Abstract
Alzheimer's disease (AD) is a complex neurodegenerative disease determined by the combination of environmental and genetic factors. The prevalence of the disease is rapidly increasing with the aging of the population in the Western world. The main genetic contributors to the disease are still unclear and no cure is available yet. The complete picture of the molecular pathologic mechanisms involved in the disease are also not resolved yet. The current hypothesis is that the disease is caused by accumulation of a toxic fragment of amyloid precursor protein (APP) called A[beta] in the neurons. This accumulation causes synaptic dysfunction and neuronal death. Our study aims at investigating the role of TrkB in modulating APP metabolism. TrkB is a receptor expressed on neurons and important in synaptic function, neuronal survival and long-term potentiation. This receptor has a functional relevance in AD and a genetic relevance since some studies associated single nucleotide polymorphisms on this gene to AD. We hypothesized that TrkB isoforms can affect APP metabolism in different ways and we tested this hypothesis in different human cell lines. We found that TrkB isoforms can alter APP glycosylation and processing and that the TrkB isoforms can interact with each other and alter their effect on APP. We also showed for the first time that TrkB SHC, one of the TrkB truncated isoforms, regulates the full-length isoform differently from TrkB T. Our work demonstrates the potential importance of TrkB in AD pathogenesis and lays ground for designing better AD therapies based on the natural TrkB ligand BDNF (Brain Derived Neurotrophic Factor).
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Details
- Title
- TrkB isoforms differentially modulate amyloid precursor protein metabolism
- Creators
- Sara Ansaloni - DU
- Contributors
- Aleister Saunders (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biology; College of Arts and Sciences; Drexel University
- Other Identifier
- 3412; 991014632693704721