Date of Graduation
12-2017
Document Type
Dissertation (PhD)
Program Affiliation
Neuroscience
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Dr. Andrew J. Bean
Committee Member
Dr. M. Neal Waxham
Committee Member
Dr. Terry Walters
Committee Member
Dr. Andrey Tsvetkov
Committee Member
Dr. Darren Boehning
Abstract
Amyloid-beta (Aβ) aggregation and deposition into extracellular plaques is a hallmark of the most common forms of dementia, including Alzheimer’s disease. The Aβ-containing plaques result from pathogenic cleavage of amyloid precursor protein (APP) by secretases resulting in intracellular production of Aβ peptides that are secreted and accumulate extracellularly. Despite considerable progress towards understanding APP processing and Aβ aggregation, the mechanisms underlying endosomal production of Aβ peptides and their secretion remain unclear. Using endosomes isolated from cultured primary neurons, we determined that the trafficking of APP from the endosomal membrane into internal vesicles of late endosome/multivesicular bodies (MVB) is dependent on Endosomal Sorting Complexes Required for Transport (ESCRT) machinery. This implied that APP is ubiquitinated to allow ESCRT interactions. We then identified that the endosome-associated E3 ubiquitin ligase, UBE4B, is required for efficient endosomal APP trafficking. These results suggest that the efficiency of endosomal APP trafficking regulates Aβ generation. Decreasing Aβ levels in the brain may be a mechanism for disease modification in amyloid-related dementia. These experiments elucidate cellular mechanisms that are amenable to regulation and could serve as potential therapeutic targets for amyloid pathologies.
Keywords
amyloid precursor protein, amyloid beta, alzheimer's disease, endosomes, ESCRT, APP, dementia, UBE4B
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