Date of Award
Doctor of Philosophy (PhD)
College of Graduate Studies
Ann Charlotte Granholm
People with Down syndrome (DS) have elevated neuroinflammation early in life and develop neuropathology by the age of twenty. Most individuals with DS go on to develop abnormal dementia and Alzheimer’s disease (AD). This dissertation is focused on biological pathways involved in DS-AD and includes studies in humans with DS and DS mouse models. Locus coeruleus (LC) noradrenergic (NE) neurons decline before other transmitter systems on the path to DS-AD, which leads to increased neuropathology and accelerated memory loss. To investigate the specific roles of LC-NE in DS-AD, designer receptors exclusively activated by designer drugs (DREADDs) were utilized in the Ts65Dn mouse model of DS to selectively stimulate or inhibit LC-NE activity. LC-NE activity modulated neuroinflammation, memory performance, and AD pathology in this mouse model. Altogether these findings implicate the importance of LC-NE function in the context of DS-AD. LC-NE dysfunction may also affect resolution response to neuroinflammation. Insufficient resolution activity was already known to correlate with AD neuropathology in humans and mouse models, but specialized pro-resolving factors have not been evaluated as a therapeutics in DS-AD. In the next portion of my thesis, I developed a novel therapeutic approach to enhance resolution activity in Ts65Dn mice with a pro-resolving mediator, resolvin E1 (RvE1). RvE1 treatment significantly reduced glial activation in the brain and pro-inflammatory cytokines in the periphery of Ts65Dn mice. RvE1 therapy reversed Ts65Dn deficits in memory and cognitive flexibility, which correlated with significant proteomic measures of the inflammatory resolution process. Finally, I investigated blood biomarkers that are relevant to AD including neuron-derived exosome levels of amyloid-beta peptides and phosphorylated-Tau (P-Tau) and serum BDNF levels. These AD biomarkers were already significantly elevated early in childhood with unique trajectories associated with dementia in humans with DS. Serum BDNF levels correlated with exosome P-Tau levels, suggesting an interaction between these two pathways in the development of DS-AD in humans. These data provide novel hope for meaningful therapeutics, to be implemented in early childhood in those with DS and inform both research and clinical perspectives at the crossroads of DS and AD.
Hamlett, Eric Daniel, "Investigations at the Crossroads of Down Syndrome and Alzheimer’s Disease" (2017). MUSC Theses and Dissertations. 331.
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