Early Evidence of Low Bone Density and Decreased Serotonergic Synthesis in the Dorsal Raphe of a Tauopathy Model of Alzheimer’s Disease
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Reduced bone mineral density (BMD) and its clinical sequelae, osteoporosis, occur at a much 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 2-6 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 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.
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Reduced bone mineral density traits are exhibited in various transgenic mouse models designed to mimic humanized AD neuropathology.
“Similar to this clinical comorbidity, reduced bone mineral density traits are exhibited in various transgenic mouse models designed to mimic humanized AD neuropathology30,31.”
From Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis (2025) · cites this paper as [31]
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- Authors
- Dengler-Crish, C. M., Smith, M. A., & Wilson, G. N.
- Affiliations
- Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
- Northeast Ohio Medical University (US)
- Kent State University (US)
- ORCID
- Smith, Matthew A.
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2016-12-20
- Volume
- 55
- Issue
- 4
- Pages
- 1605-1619
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- PMC
- PMC5181667
- OpenAlex
- W2547969205
- Cited by
- 61
- References
- 66
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 7 · 2023: 8 · 2022: 6 · 2021: 5 · 2020: 6 · 2019: 14 · 2018: 5 · 2017: 1
- FWCI
- 5.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Alzheimer s Disease (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- Alzheimer's disease, bone mineral density
- MeSH terms
- Age Factors, Alzheimer Disease, Animals, Body Composition, Body Weight, Bone Diseases, Disease Models, Animal, Female, Male, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Phosphorylation, Serotonin, Tryptophan Hydroxylase, Bone Density, tau Proteins, Tauopathies, Mice, Dorsal Raphe Nucleus
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