Journal of Alzheimer's disease : JAD

Early Evidence of Low Bone Density and Decreased Serotonergic Synthesis in the Dorsal Raphe of axa0Tauopathy Model of Alzheimer's Disease.

PMID 27814296


Reduced bone mineral density (BMD) and its clinical sequelae, osteoporosis, occur at axa0much greater 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 2-6xa0months of age-time-points prior to the presence of significant tauopathy in the hippocampal/entorhinal regions characteristic of this model. We found axa0significantly 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 axa070% reduction in TPH-positive cells in the dorsal raphe nucleus (DRN)-axa0pivotal 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 4xa0months of age in htau mice. Together, these findings demonstrate that reduced BMD occurs earlier than overt degeneration in axa0tau-based AD model and that pathological changes in tau phosphorylation occur in the serotonin-producing neurons of the brainstem raphe in these mice. This illuminates axa0need to define axa0mechanistic relationship between bone loss and serotonergic deficits in early AD.