Amyloid-β neuropathology induces bone loss in male mice by suppressing bone formation and enhancing bone resorption
Younghun Jung,
Birol Ay,
Sajin M. Cyr,
Christina M. Tognoni,
Kaitlin Klovdahl,
Julia Matthias,
Qiuxia Cui,
Daniel J. Brooks,
Mary L. Bouxsein,
Isabel Carreras,
Alpaslan Dedeoglu,
Murat Bastepe
Affiliations
Younghun Jung
The Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Veterans Affairs, VA Boston Healthcare System, Boston, MA 02130, USA; Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA
Birol Ay
The Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Sajin M. Cyr
The Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Christina M. Tognoni
Department of Veterans Affairs, VA Boston Healthcare System, Boston, MA 02130, USA; Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA
Kaitlin Klovdahl
The Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Julia Matthias
The Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Qiuxia Cui
The Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Daniel J. Brooks
The Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Orthopedic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
Mary L. Bouxsein
The Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Orthopedic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
Isabel Carreras
Department of Veterans Affairs, VA Boston Healthcare System, Boston, MA 02130, USA; Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA; Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA
Alpaslan Dedeoglu
Department of Veterans Affairs, VA Boston Healthcare System, Boston, MA 02130, USA; Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA; Department of Radiology, Massachusetts General Hospital and Harvard Medical School, MA 02114, USA
Murat Bastepe
The Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Corresponding author at: Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, 55 Fruit St, Boston, MA 02114, USA.
Alzheimer's disease (AD) and osteoporosis often coexist in the elderly. Although observational studies suggest an association between these two diseases, the pathophysiologic link between AD and skeletal health has been poorly defined. We examined the skeletal phenotype of 5xFAD mice, an AD model with accelerated neuron-specific amyloid-β accumulation causing full-blown AD phenotype by the age of 8 months. Micro-computed tomography indicated significantly lower trabecular and cortical bone parameters in 8-month-old male, but not female, 5xFAD mice than sex-matched wild-type littermates. Dynamic histomorphometry revealed reduced bone formation and increased bone resorption, and quantitative RT-PCR showed elevated skeletal RANKL gene expression in 5xFAD males. These mice also had diminished body fat percentage with unaltered lean mass, as determined by dual-energy X-ray absorptiometry (DXA), and elevated Ucp1 mRNA levels in brown adipose tissue, consistent with increased sympathetic tone, which may contribute to the osteopenia observed in 5xFAD males. Nevertheless, no significant changes could be detected between male 5xFAD and wild-type littermates regarding the serum and skeletal concentrations of norepinephrine. Thus, brain-specific amyloid-β pathology is associated with osteopenia and appears to affect both bone formation and bone resorption. Our findings shed new light on the pathophysiologic link between Alzheimer's disease and osteoporosis.
