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Summary: Researchers report on a link between bone mineral density and serotonergic synthesis in preclinical models of Alzheimer’s disease.
Researchers at NEOMED have just identified a major connection between areas of the brainstem – the ancient area that controls mood, sleep and metabolism – and detrimental changes to bone in a preclinical model of Alzheimer’s disease (AD). The study, titled “Early Evidence of Low Bone Density and Decreased Serotonergic Synthesis in the Dorsal Raphe of a Tauopathy Model of Alzheimer’s Disease,” is led by Christine Dengler-Crish, Ph.D., assistant professor of pharmaceutical sciences, and anatomy and neurobiology, and will be published in the upcoming issue of the Journal of Alzheimer’s Disease, an international multidisciplinary journal that reports progress in understanding the causes, symptoms, and treatment of Alzheimer’s.
More than five million Americans are living with Alzheimer’s disease. Along with being the sixth leading cause of death in the U.S., Alzheimer’s has major social, emotional and financial consequences for patients and their families. Incurable and seemingly unstoppable, less than 5 percent of AD cases are due to a clear genetic reason, so it is hard to predict who will be at risk for acquiring this devastating disease./.../
Early Evidence of Low Bone Density and Decreased Serotonergic Synthesis in the Dorsal Raphe of a Tauopathy Model of Alzheimer’s Disease
Reduced bone mineral density (BMD) and its clinical sequelae, osteoporosis, occur at a much greater rate the rate in patients with Alzheimer’s disease (AD), often emerging early in the disease before significant cognitive decline is seen. Reduced BMD translates to increased bone fracture risk, decreased quality of life, and increased mortality for AD patients. However, the mechanism responsible for this observation is unclear. We hypothesize that bone loss is an additional component of an AD prodrome, changes that emerge prior to dementia and are mediated by dysfunction of the central serotonergic pathways. We characterized the skeletal phenotype of htau mice that express human forms of the microtubule-associated protein tau that become pathologically hyperphosphorylated in AD. Using radiographic densitometry, we measured BMD in female and male htau mice from 2–6 months of age–time-points prior to the presence of significant tauopathy in the hippocampal/entorhinal regions characteristic of this model. We found a significantly reduced BMD phenotype in htau mice that was most pronounced in males. Using western blotting and immunofluorescence, we showed overall reduced tryptophan hydroxylase (TPH) protein in htau brainstem and a 70% reduction in TPH-positive cells in the dorsal raphe nucleus (DRN)–a pivotal structure in the regulation of the adult skeleton. Elevations of hyperphosphorylated tau (ptau) proteins were also measured in brainstem, and co-labeled immunofluorescence studies showed presence of ptau in TPH-positive cells of the DRN as early as 4 months of age in htau mice. Together, these findings demonstrate that reduced BMD occurs earlier than overt degeneration in a tau-based AD model and that pathological changes in the tau phosphorylation occur in the serotonin-producing neurons of the brainstem raphe in these mice. This illuminates a need to define a mechanistic relationship between bone loss and serotonergic deficits in early AD.
“Early Evidence of Low Bone Density and Decreased Serotonergic Synthesis in the Dorsal Raphe of a Tauopathy Model of Alzheimer’s Disease” by Dengler-Crish, Christine M.; Smith, Matthew A.; and Wilson, Gina N. in Journal of Alzheimer’s Disease. November 3 2016 doi:10.3233/JAD-160658