Osteoporosis is negatively correlated with body mass, whereas both
osteoporosis and
weight loss occur at higher incidence during the progression of
Alzheimer's disease (AD) than the age-matched non-
dementia individuals. Given that there is no evidence that being
overweight is associated with AD-type
cognitive dysfunction, we hypothesized that moderate
weight gain might have a protective effect on the bone loss in AD without exacerbating
cognitive dysfunction. In this study, feeding a high-fat diet (HFD, 45% calorie from fat) to female APP/PS1 transgenic mice, an AD animal model, induced
weight gain. The bone mineral density, microarchitecture, and biomechanical properties of the femurs were then evaluated. The results showed that the middle-aged female APP/PS1 transgenic mice were susceptible to
osteoporosis of the femoral bones and that
weight gain significantly enhanced bone mass and mechanical properties. Notably, HFD was not detrimental to brain
insulin signaling and AβPP processing, as well as to exploration ability and working, learning, and memory performance of the transgenic mice measured by T maze and Morris water maze, compared with the mice fed a normal-fat diet (10% calorie from fat). In addition, the circulating levels of
leptin but not
estradiol were remarkably elevated in HFD-treated mice. These results suggest that a
body weight gain induced by the HFD feeding regimen significantly improved bone mass in female APP/PS1 mice with no detriments to exploration ability and spatial memory, most likely via the action of elevated circulating
leptin.