MON-713 Gene-dose-dependent reduction of FSHR expression rescues bone density, body fat, and recognition memory in an Alzheimer’s disease mouse model

Abstract Disclosure: U. Cheliadinova: None. S.L. Sims: None. F. Korkmaz: None. D. Vasilyeva: None. G. Pevnev: None. J. Gimenez Roig: None. G. Burganova: None. S. Parte: None. O. Barak: None. V. Laurencin: None. Z.B. Tumoglu: None. A. Gumerova: None. F. Sultana: None. W. Zhou: None. Y. Wei: None. A.R. Pallapati: None. R. Latif: None. F. Fueyo Gonzalez: None. S. Rojekar: None. O. Moldavski: None. D. Lizneva: None. V. Ryu: None. T. Frolinger: None. T. Yuen: None. M. Zaidi: None. Background: Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder of progressive dementia, affecting approximately 6.5 million Americans. Metabolic changes are associated with neurodegeneration and have been linked to AD via abnormal glucose metabolism and the dysregulation of amino acids, fatty acids, and lipids. Follicle-stimulating hormone (FSH) levels have been linked to changes in body and bones composition. Elevated FSH levels are associated with higher total fat body mass in post-menopausal women in accordance with higher risk of development of AD disease, while conversely, reducing FSH levels has been shown to improve cognitive and learning function. Our recent study showed reduction of FSH-receptor (FSHR) improves memory performance in AD mice. Taken together, in this study we aimed to study the impact of FSHR on body composition and bone mineral density in Alzheimer’s disease mouse model. Methods: We generated female 3xTg;Fshr+/+, 3xTg;Fshr+/−, and 3xTg;Fshr−/− mice (10-12 mice/group) by crossing 3xTg mice with Fshr−/− mutants. 3xTg; Fshr−/− mice received 90-day, slow-release pellets containing 0.36 mg 17β-estradiol to normalize their estrogen level. Body composition (fat, lean, and total mass) and bone density at various sites (femur, tibia and L3-L6 spine) were assessed using quantitative NMR and dual-energy X-ray absorptiometry (DXA), respectively, at 5.5-7 months. and 9.5-11 months of age. Body composition was determined again when the mice were 5.5-7 months old. To assess recognition memory, we used the Novel Object Recognition (NOR) test. Results: At 5.5-7 months of age, 3xTg;Fshr−/− mice displayed a significant decrease in fat mass compared to 3xTg;Fshr+/− (P=0.012) and 3xTg;Fshr+/+ (P=0.009), while total mass did not differ between groups. The 3xTg;Fshr−/− mice also displayed a higher bone mineral density (BMD), with the most significant differences observed in the right tibia (P=0.001, vs 3xTg;Fshr+/−, and P=0.012, vs 3xTg;Fshr+/+ mice). Conversely, BMD in the L3-L6 spine was lower in 3xTg;Fshr−/− mice compared to 3xTg;Fshr+/− (P=0.087) and 3xTg;Fshr+/+ (P=0.0003). At 9.5-11 months, fat mass remained significantly lower in 3xTg;Fshr−/− mice compared to 3xTg;Fshr+/− (P=0.032) or 3xTg;Fshr+/+ (P=0.045). These changes were accompanied by a rescue of recognition memory decline in 3xTg;Fshr−/− mice in comparison with both 3xTg;Fshr+/+ and 3xTg;Fshr+/− mice in the NOR test. Conclusions: Our study using the AD mouse model suggests that FSHR expression negatively impacts BMD and body composition while rescuing recognition memory. These findings will provide a novel direction to evaluate the role of FSH in the pathophysiology and intervention in AD. Presentation: Monday, July 14, 2025