Presenilin L166P Mutation, a Model of Familial Alzheimer's Disease, Leads to Early Onset Bone Loss

Abstract

Accelerated bone loss has been reported in the early stages of Alzheimer's disease (AD) as indicated by reduced bone mineral density and increased fracture risk in these patients, compared to healthy individuals. In the present study, we investigated bone loss in mouse models of familial Alzheimer's disease harboring the Presenilin 1 (L166P) knock-in mutation (PSEN1 KI), with or without the human amyloid precursor protein transgene (hAPP Tg+) known to induce brain amyloid pathology by 6 months. Female and not male 12-month PSEN1/hAPP Tg+ mice exhibited reduced whole-body bone mineral density and bone mineral content, compared to sex-matched controls. Consistent with PSEN1 L166P driving the phenotype, female PSEN1 KI mice lacking the hAPP transgene also displayed low bone mass with a reduction in bone microarchitecture observed as early as 1 month of age. Correspondingly, PSEN1 KI mice exhibit reduced cortical and trabecular bone mass compared to age- and sex-matched control mice. The loss of bone microarchitecture was largely attributed to a reduction in bone formation as indicated by decreases in serum P1NP levels and osteoblast ALP activity and mRNA expression in vitro. At the ages examined, PSEN1 KI mice exhibited increased follicle stimulating hormone (FSH) levels, which is known to cause a decrease in bone mass. Western blotting also identified both PSEN1 and amyloid-beta protein expression in bone and brain tissue. Taken together, the data indicate that female-specific bone loss in familial AD is potentially due to the direct actions of mutant PSEN1 in bone cells combined with systemic crosstalk caused by brain-expressed PSEN1 L116P.