Biology and Biomedical Sciences: Molecular Cell Biology
Date of Award
Doctor of Philosophy (PhD)
Chair and Committee
John R Cirrito
A diagnosis of Alzheimer's disease is one of the most devastating things one can hear. This terrible disease robs people of their ability to remember cherished events as their brains become riddled with beta amyloid plaques. Alzheimer's is especially terrifying because there currently are no effective treatments for slowing or stopping the disease. However, recent research has shown that plaque formation is correlated to concentrations of amyloid beta. This discovery suggests that limiting amyloid beta production could potentially halt the disease. One promising avenue for slowing amyloid beta production is serotonergic signaling.
This dissertation presents evidence for a direct sequence of signaling events from serotonin receptors to reduction of amyloid beta by alpha-secretase. Two serotonin receptors, 5-HT4R and 5-HT7R, reduce amyloid beta levels in the brains of transgenic mice that model Alzheimer's disease. These receptors are linked to activation of PKA, and blocking PKA activity increases amyloid levels in mice. PKA leads to activation of ERK, a kinase which acts in both the nucleus and the cytoplasm. We show SSRI antidepressant treatment fails to produce changes in gene expression which suggests ERK acts within the cytoplasm to reduce amyloid beta. Finally, we show that selective inhibition of ADAM10, the primary alpha-secretase, is unable to block the beneficial effects of SSRI antidepressants in transgenic mice. These discoveries explain the mechanisms regulating amyloid beta reduction by serotonin activity and also offer a more selective therapy for Alzheimer's disease.
Fisher, Jonathan Robert, "Serotonergic Signaling Pathways that Suppress Amyloid Beta in Mouse Models of AD" (2014). All Theses and Dissertations (ETDs). 1301.