High post-menopausal levels of the pituitary gonadotropin follicle-stimulating hormone (FSH) are strongly associated with the onset of Alzheimer’s disease (AD). We have shown recently that FSH directly activates the hippocampal FSH receptors (FSHRs) to drive AD-like pathology and memory loss in mice. To unequivocally establish a role for FSH in memory loss, we depleted the Fshr on a 3xTg background and utilized Morris Water Maze to study deficits in spatial memory. 3xTg;Fshr^+/+ mice displayed impaired spatial memory at 5 months of age. The loss of memory acquisition and retrieval were both rescued in 3xTg;Fshr^−/− mice and, to a lesser extent, in 3xTg;Fshr^+/− mice—documenting clear gene–dose-dependent prevention of spatial memory loss. Furthermore, at 5 and 8 months, sham-operated 3xTg;Fshr^−/− mice showed better memory performance during the learning and/or retrieval phases, further suggesting that Fshr deletion prevents age-related progression of memory deficits. This prevention was not seen when mice were ovariectomized, except in the 8-month-old 3xTg;Fshr^−/− mice. There was also a gene–dose-dependent reduction mainly in the amyloid β40 isoform in whole brain extracts. Finally, serum FSH levels <8 ng/mL in 16-month-old APP/PS1 mice were associated with better retrieval of spatial memory. Collectively, the data provide compelling genetic evidence for a protective effect of inhibiting FSH signaling on the progression of spatial memory deficits in mice and lay a firm foundation for the use of an FSH-blocking agent for the early prevention of memory loss in post-menopausal women.

绝经后垂体促性腺激素促卵泡激素 （FSH） 水平高与阿尔茨海默病 （AD） 的发病密切相关。我们最近表明，FSH 直接激活海马 FSH 受体 （FSHRs） 以驱动小鼠的 AD 样病理和记忆丧失。为了明确 FSH 在记忆丧失中的作用，我们在 3xTg 背景上耗尽了 FSHR，并利用莫里斯水迷宫来研究空间记忆的缺陷。3xTg;Fshr^+/+ 小鼠在 5 个月大时表现出空间记忆受损。记忆获取和检索的损失均在 3xTg 中得到挽救;Fshr ^{- / -} 小鼠，在较小程度上，在 3xTg 中;Fshr ^{+ / -} 小鼠 - 记录了明确的基因剂量依赖性空间记忆丧失预防。此外，在 5 个月和 8 个月时，假手术 3xTg;Fshr^-/-小鼠在学习和/或检索阶段表现出更好的记忆表现，进一步表明 Fshr 缺失可以防止与年龄相关的记忆缺陷进展。当小鼠切除卵巢时未观察到这种预防，除了 8 个月大的 3xTg;Fshr^-/-小鼠。全脑提取物中的淀粉样蛋白 β40 亚型也存在基因剂量依赖性减少。最后，16 月龄 APP/PS1 小鼠血清 FSH 水平 <8 ng/mL 与空间记忆的更好检索相关。 总的来说，这些数据为抑制 FSH 信号对小鼠空间记忆缺陷进展的保护作用提供了令人信服的遗传证据，并为使用 FSH 阻断剂早期预防绝经后妇女的记忆丧失奠定了坚实的基础。