Gene-dose-dependent reduction of Fshr expression improves spatial memory deficits in Alzheimer's mice

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