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

Authors

Uliana Cheliadinova, Instuitute for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Steven Sims, Instuitute for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Funda Korkmaz, Instuitute for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Darya Vasilyeva, Instuitute for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Victoria Laurencin, Instuitute for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Judit Gimenez-Roig, Instuitute for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Georgii Pevnev, Instuitute for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Guzel Burganova, Instuitute for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Clifford J. Rosen, MaineHealth Institute for Research, Scarborough, ME.Follow

Document Type

Article

Publication Date

12-16-2025

Institution/Department

Center for Molecular Medicine

Journal Title

Molecular psychiatry

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 Fshr genotypes. 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 Fshr genotypes 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;Fshr and APP-KI;Fshr mice, but not in male mice. Likewise, female, but not male 3xTg;Fshr mice 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 Fshr mice showed reduced fat mass at the early, but not the late time point. DXA revealed that female, but not male APP-KI;Fshr mice 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.

Recommended Citation

Cheliadinova, Uliana; Sims, Steven; Korkmaz, Funda; Vasilyeva, Darya; Laurencin, Victoria; Gimenez-Roig, Judit; Pevnev, Georgii; Burganova, Guzel; and Rosen, Clifford J., "Fshr gene depletion prevents recognition memory loss, fat accrual and bone loss in Alzheimer's mice" (2025). MaineHealth Maine Medical Center. 4240.
https://knowledgeconnection.mainehealth.org/mmc/4240