A Striking Bone Phenotype in the Familial Danish Dementia (FDD) Tg+ Mouse

Abstract

Familial Danish Dementia (FDD) is an autosomal dominant neurodegenerative disease caused by a 10‐nucleotide insertion mutation in the BRI(2) gene (aka ITM2B) resulting in a frame‐shift. The resulting Danish amyloid precursor protein (ADanPP) is then cleaved an amyloidogenic peptide that deposits in the brain and cerebral vessels. FDD in patients results in a range of clinical defects, including cataracts, hearing defects, cerebellar ataxia, slurred speech, gait disturbances, psychosis, and dementia. With emerging evidence that human bone defects are associated with neurodegenerative disease, we phenotyped bone in 12‐month FDD Tg+ mice. FDD Tg+ mice exhibit abnormal grooming by 9 months and have Ab plaques and behavior deficits by 12 months, paralleling mechanisms in Alzheimer disease. At 12 months of age, femurs from FDD Tg+ mice were assessed by mCT (SkyScan 1172, 9 mm resolution) in the distal metaphysis (1 mm) and mid‐diaphysis regions for trabecular and cortical areas, respectively. Both male and female femurs exhibited significantly reduced bone volumes (44%) vs. age‐, strain‐matched wildtype mice; male FDD Tg+ femurs showed a 24% reduction in bone mineral density.Trabecular boneFemales FDD Tg+ femurs had a 24% reduction in the trabecular thickness (vs. controls), whereas male FDD Tg+ femurs exhibited a 24% increase in the trabecular separation and 40% reduction in the trabecular number (vs. controls).Cortical boneFemale FDD Tg+ femurs had a 15% reduction in bone marrow area and 8.6% endocortical thickness compared to controls. Male FDD Tg+ femurs had reduced total cross‐sectional area and endocortical thickness by about 8%, a 15% reduction in the marrow area, along with a reduced periosteal thickness and increased cortical thickness vs. controls. These results indicate that FDD Tg+ mice have significant bone phenotypes in parallel with previously observed brain defects, suggesting therapeutic interventions may want to consider how neurodegeneration might impact other critical organs in the body such as bone.Support or Funding InformationLilly Foundation/Indiana Center for Musculoskeletal Health/ IU School of Medicine, Physician Scientist Initiative, Scientific Research Initiative