Fshr gene depletion prevents recognition memory loss, fat accrual and bone loss in Alzheimer's mice.

Abstract

Epidemiologic evidence links follicle-stimulating hormone (FSH), a pituitary glycoprotein that rises during menopause, to memory loss, fat accumulation, and bone loss. We and others have shown that the attenuation of FSH signaling, either genetically or pharmacologically, prevents memory loss, fat accrual, and bone loss in multiple mouse models. Here, we investigated whether the genetic depletion of the FSH receptor (Fshr) affects recognition memory, body composition, and bone mineral density (BMD) in two AD mouse models. We generated male and female 3xTg and APP-KI mice carrying the Fshr, Fshr, and Fshrgenotypes. Recognition memory was evaluated using the Novel Object Recognition (NOR) test. Body composition (fat, lean, and total mass) and site-specific bone mineral density (femur, tibia, L3-L5 spine) measurements were made using quantitative nuclear magnetic resonance (qNMR) and dual-energy X-ray absorptiometry (DXA), respectively, at two time points. Given that female Fshrgenotypes are otherwise hypogonadal, they were implanted with 17β-estradiol pellets at 8-12 weeks of age to normalize serum estrogen. At the early time point, the deficit in recognition memory was rescued in female 3xTg;Fshrand APP-KI;Fshrmice, but not in male mice. Likewise, female, but not male 3xTg;Fshrmice showed reduced fat mass at both the early and later time points, but without changes in total body mass. In contrast, in the APP-KI cohort, both female and male Fshrmice showed reduced fat mass at the early, but not the late time point. DXA revealed that female, but not male APP-KI;Fshrmice showed progressive increases with time in BMDs in tibiae, femora, and vertebrae, which were either statistically significant or approached significance. This phenotype was not observed on the 3xTg background. These studies constitute the first report for time- and strain-dependent effects of global Fshr depletion in the same mouse, setting the stage for the simultaneous prevention, using a single therapeutic, of three disorders of public health magnitude-Alzheimer's disease, obesity and osteoporosis.