8734 Absent FSH Signaling Rescues Spatial and Recognition Memory Impairments in Female 3xTg Mice

Abstract Disclosure: S. Sims: None. F. Sen: None. F. Sultana: None. A. Liu: None. V. Laurencin: None. A. Gumerova: None. O. Barak: None. S. Rojekar: None. A.R. Pallapati: None. L. Cullen: None. R. Chen: None. K. Goosens: None. V. Ryu: None. T. Yuen: None. M. Zaidi: None. T. Frolinger: None. F. Korkmaz: None. Alzheimer’s disease (AD) is a major progressive neurodegenerative disorder of the aging population, accounting for more than 60-80% of dementia cases. High serum level of the pituitary gonadotropin, follicle-stimulating hormone (FSH), is strongly associated with the onset of AD. We recently showed that FSH activates hippocampal Fshr to drive AD–like pathology and cognitive impairment in AD mice, that FSH blockade in these mice abrogates the AD-like phenotype by inhibiting the neuronal C/EBPβ–δ-secretase pathway, and that FSH and ApoE4, the most prevalent genetic risk factor of AD, jointly trigger AD-like pathogenesis by activating C/EBPβ-δ-secretase signaling. To further confirm the role of FSH in AD cognitive decline, we used female 3xTg;Fshr+/+, 3xTg;Fshr+/– and 3xTg;Fshr–/– mice that underwent sham surgery or ovariectomy (OVX) at 8 weeks of age. Sham-operated 3xTg;Fshr–/– mice were implanted with 17β-estradiol pellets to normalize E2 levels. Morris Water Maze (MWM) and Novel object recognition (NOR) tests were perform in these mice to assess spatial and recognition memory, respectively. 3xTg;Fshr+/+ mice displayed impaired spatial memory at 5-month of age in the MWM test. This impairment, in both the learning and retrieval phases, is significantly ameliorated in 3xTg;Fshr–/– mice and to a lesser extent in 3xTg;Fshr+/– mice, suggesting that Fshr expression has a negative impact on memory. At 5 and 10 months of age, sham-operated 3xTg;Fshr–/– mice show better memory performance in the MWM test during the learning phase when compared to their wild-type littermates, suggesting a rescue of spatial memory and progression with age. However, this rescue was not seen when mice were ovariectomized. At 5 months of age, sham-operated 3xTg;Fshr–/– mice displayed better memory retrieval compared with 3xTg;Fshr+/+ mice. This effect was not observed when the mice were 10-month-old, suggesting that the beneficial effect of the absence of FSH signaling on memory consolidation could be masked by disease severity and older age. OVX 3xTg;Fshr+/+, 3xTg;Fshr+/– mice displayed a decline in memory consolidation at 10-months of age compared with 5-month of age, while the 3xTg;Fshr–/– mice showed a significantly slower decline. Using the NOR test, we found impaired recognition memory in 10-month-old sham-operated or OVX 3xTg;Fshr+/+ and 3xTg;Fshr+/– mice; this effect was prevented in OVX 3xTg;Fshr–/– mice. Finally, 3xTg;Fshr–/– mice displayed lower Aβ40 and Aβ42 levels in the brain (ELISA). Altogether, our results confirm a protective effect of absent Fshr signaling on spatial learning, consolidation, memory retrieval, recognition memory and reduction of brain Aβ40 and Aβ42. Presentation: 6/1/2024