Early Evidence of Low Bone Density and Decreased Serotonergic Synthesis in the Dorsal Raphe of a Tauopathy Model of Alzheimer's Disease.
Female; Male; Animals; Mice; *Alzheimer's disease; Body Weight; Body Composition; Age Factors; Body Weight/genetics; Phosphorylation; Bone Density/*physiology; *Alzheimer Disease/complications/genetics/pathology; *bone density; *microtubule-associated protein; *serotonin; *tau proteins; *tauopathies; Body Composition/genetics; Bone Diseases/*etiology; Dorsal Raphe Nucleus/*pathology; Neurons/metabolism/pathology; Serotonin/*metabolism; tau Proteins/*genetics/metabolism; Tauopathies/complications/genetics; Tryptophan Hydroxylase/metabolism; Biological; Models; Inbred C57BL; Animal; Disease Models; Transgenic; Nerve Tissue Proteins; Neurodegenerative Diseases; Animal Studies; Alzheimer's Disease; Bone Density – Physiology; Nerve Tissue Proteins – Metabolism; Neurodegenerative Diseases – Complications; Alzheimer's Disease – Complications; Alzheimer's Disease – Pathology; Bone Diseases – Etiology; Brain Stem – Pathology; Neurons – Metabolism; Neurons – Pathology; Oxidoreductases – Metabolism; Serotonin – Metabolism
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
Dengler-Crish Christine M; Smith Matthew A; Wilson Gina N
Journal of Alzheimer's disease : JAD
2017
1905-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3233/JAD-160658" target="_blank" rel="noreferrer noopener">10.3233/JAD-160658</a>
Genetically enhancing the expression of chemokine domain of CX3CL1 fails to prevent tau pathology in mouse models of tauopathy.
Alzheimer's disease; Animal; Animals; Antigens; Biological; Calcium Binding Proteins – Metabolism; Calcium-Binding Proteins/metabolism; Cells – Drug Effects; Cells – Metabolism; Cells – Pathology; Chemokine CX3CL1/*genetics/metabolism; Cognition Disorders – Etiology; Cognition Disorders/etiology; CX3CL1; CX3CR1; Cytokines; Cytokines – Metabolism; Cytokines/metabolism; Differentiation/genetics/metabolism; Disease Models; Gene Expression Regulation/drug effects/*genetics; Genes; Genes – Drug Effects; Learning; Lipopolysaccharides; Lipopolysaccharides/toxicity; Maze Learning; Mice; Microfilament Proteins – Metabolism; Microfilament Proteins/metabolism; Microglia; Microglia/drug effects/*metabolism/pathology; Models; Mutation; Mutation/genetics; Nerve Tissue Proteins; Nerve Tissue Proteins – Metabolism; Neurodegenerative Diseases; Neurodegenerative Diseases – Complications; Neurodegenerative Diseases – Pathology; Neuroinflammation; Surface; Surface – Metabolism; Tau; tau Proteins/genetics/metabolism; Tauopathies; Tauopathies/complications/genetics/*pathology; Transgenic
BACKGROUND: Fractalkine (CX3CL1) and its receptor (CX3CR1) play an important role in regulating microglial function. We have previously shown that Cx3cr1 deficiency exacerbated tau pathology and led to cognitive impairment. However, it is still unclear if the chemokine domain of the ligand CX3CL1 is essential in regulating neuronal tau pathology. METHODS: We used transgenic mice lacking endogenous Cx3cl1 (Cx3cl1(-/-)) and expressing only obligatory soluble form (with only chemokine domain) and lacking the mucin stalk of CX3CL1 (referred to as Cx3cl1(105Delta) mice) to assess tau pathology and behavioral function in both lipopolysaccharide (LPS) and genetic (hTau) mouse models of tauopathy. RESULTS: First, increased basal tau levels accompanied microglial activation in Cx3cl1(105Delta) mice compared to control groups. Second, increased CD45(+) and F4/80(+) neuroinflammation and tau phosphorylation were observed in LPS, hTau/Cx3cl1(-/-), and hTau/Cx3cl1(105Delta) mouse models of tau pathology, which correlated with impaired spatial learning. Finally, microglial cell surface expression of CX3CR1 was reduced in Cx3cl1(105Delta) mice, suggesting enhanced fractalkine receptor internalization (mimicking Cx3cr1 deletion), which likely contributes to the elevated tau pathology. CONCLUSIONS: Collectively, our data suggest that overexpression of only chemokine domain of CX3CL1 does not protect against tau pathology.
Bemiller Shane M; Maphis Nicole M; Formica Shane V; Wilson Gina N; Miller Crystal M; Xu Guixiang; Kokiko-Cochran Olga N; Kim Ki-Wook; Jung Steffen; Cannon Judy L; Crish Samuel D; Cardona Astrid E; Lamb Bruce T; Bhaskar Kiran
Journal of neuroinflammation
2018
2018-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1186/s12974-018-1310-6" target="_blank" rel="noreferrer noopener">10.1186/s12974-018-1310-6</a>