Damage to the Locus Coeruleus in Alzheimer's Disease: Potential Causes and Therapeutic Targets
Braun, David J.
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Therapeutic options for Alzheimer's disease (AD) are limited, and this dearth of treatments necessitates the development of novel therapeutic targets. One such target is the noradrenergic locus coeruleus (LC), a small nucleus located in the brainstem pons. The LC undergoes severe degeneration in AD, however the reasons for this are currently unknown. To address this question, the present dissertation is divided into three parts. In the first, I depleted brain derived neurotrophic factor (BDNF) from the hippocampus (HC) of 5xFAD AD model mice. The resulting decline in LC projections throughout LC target regions, as well as reductions in biosynthetic enzymes for noradrenaline synthesis, indicate that BDNF in the HC is important in maintaining LC function in the AD context. In the second part I tested the LC-targeting drug vindeburnol in 5xFAD mice, known to increase noradrenaline output from LC neurons. Vindeburnol reduced amyloid pathology, raised hippocampal neurotrophin levels, and rescued behavioral deficits in anxiety-type behaviors. In the third part, I studied the mechanism of action of vindeburnol in cell culture, and found that it has phosphodiesterase inhibitor activity. Its effects on LC neurons appear to be due to signaling via the cyclic adenosine monophosphate/protein kinase A pathway. This dissertation enhances the therapeutic potential of the LC by indicating an underlying cause of its damage in the AD context, shows proof of principle of benefit of direct targeting of the LC system, and provides the basis for structure-activity relationship studies to improve the efficacy of future LC-targeting drug development.