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.
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Data are available from the corresponding authors on reasonable request.
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Acknowledgements
MZ, CJR, TY, KAG, VR and WZ acknowledge the support from the National Institutes of Health (NIH), namely R01 AG074092, U01 AG073148 and R01 AG071870 to MZ, and TY, U19 AG060917 to MZ and CJR, RF1 AG093773 to KAG and MZ, and R61 AG094602 to TY, KAG, VR, WZ and MZ. MZ and TY also acknowledge the Hevolution Foundation for support.
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Conceptualization: TY, MZ. Supervision: TF, TY, MZ. Scientific input: KG, CJR, VR, WZ. Neurobehavioral studies: SS, TF. Body Composition Assessment: UC, AS, AL, JGR, ZT, SP, SS. Data analysis: UC, TF, DV, FK, SS, FS, VL, OM, ARP, SR, TY. Animal maintenance: UC, TL, FK, DV. Methodology: TF, TY. Quality assurance: AG, GP, GB, AM, SH, YW, OB, DL, Manuscript preparation: UC, SS, TF, TY, MZ. Funding acquisition: TY, CJR, MZ, KG, VR, WZ.
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Competing interests
MZ is an inventor on issued patents on inhibiting FSH for the prevention and treatment of osteoporosis and obesity (U.S. patents 8,435,948 and 11,034,761). MZ is also an inventor on a patent application on the composition and use of humanized monoclonal anti-FSH antibodies and is a co–inventor of a pending patent on the use of FSH as a target for preventing Alzheimer disease. MZ, SR and TY are co–inventors on a pending patent relating to the ultra–high formulation of an FSH-blocking antibody. DL, MZ and TY are co–inventors of a pending patent relating to LH and body composition. These patents are owned by Icahn School of Medicine at Mount Sinai (ISMMS), and the inventors and co–inventors would be recipients of royalties, per institutional policy. MZ also consults for several financial platforms, including Gerson Lehman Group and Guidepoint, on drugs for osteoporosis and genetic bone diseases. The other authors declare no competing interests.
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All methods were performed in accordance with the relevant guidelines and regulations. Animal handling and use were compliant with the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals, and approved by the Icahn School of Medicine at Mount Sinai Institutional Animal Care and Use Committee (IACUC Approval # 2018-0047).
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Figure S3: No Side Preference Observed During Training Trial Prior to Novel Object Recognition Test in APP-KI and 3xTg Female Fshr Mutants.
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Cheliadinova, U., Sims, S., Korkmaz, F. et al. Fshr gene depletion prevents recognition memory loss, fat accrual and bone loss in Alzheimer’s mice. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03424-z
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DOI: https://doi.org/10.1038/s41380-025-03424-z
