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Description
Alzheimer’s disease (AD) is the world’s leading cause of dementia and is the sixthleading cause of death in the United States. While AD has been studied for over a century, little progress has been made in terms of treating or preventing disease progression; therefore, new therapeutic drug targets must be identified. Current clinical trials focus on inhibiting Beta- Secretase 1 (BACE1), the major enzyme involved in the formation of the amyloid beta (Abeta) peptide fragments that aggregate to form insoluble plaques in the brains of AD patients. However, many of these clinical trials have been halted due to neurological effects or organ damage with no substantial cognitive improvements. Because the current leading theory of AD is that the buildup of amyloid plaques leads to metabolic changes that result in the intraneuronal accumulation of hyperphosphorylated Microtubule Associated Protein Tau (TAU, encoded by the MAPT gene), which causes cell death resulting in brain atrophy and dementia (known as the Amyloid Cascade Hypothesis), identifying drug targets that modulate Amyloid Precursor Protein (APP) processing – without directly inhibiting BACE1 – may prove to be a viable treatment. In this work, the role of the Adenosine triphosphate Binding Cassette subfamily C member 1 (ABCC1) was studied in the context of AD. Rare mutations in ABCC1 were identified in a familial case of late-onset AD and in a sporadic case of early-onset AD, and previous laboratories have demonstrated that Abeta is a substrate for ABCC1-mediated export. Although the final experiments reveal no significant difference between the mutant and reference alleles, the data demonstrate that overexpression of ABCC1 modulates APP processing, resulting in decreased Abeta formation and increased alpha- secretase cleavage of the APP molecule, likely via transcriptional modulation of genes that are capable of altering APP metabolism. Therefore, pharmacological interventions that increase either ABCC1 expression or activity may be capable of halting, reversing, or preventing disease progression. Many cancer drug development pipelines have been employed to identify compounds that decrease ABCC1 expression or activity, and it is likely that compounds have been identified that have the opposite effect. These drugs should be studied in the context of Alzheimer’s disease.
ContributorsJepsen, Wayne Mathew (Author) / Huentelman, Matthew (Thesis advisor) / Kusumi, Kenro (Thesis advisor) / Jensen, Kendall (Committee member) / Newbern, Jason (Committee member) / Arizona State University (Publisher)
Created2021