Molecular events during the induction of neurodegeneration and memory loss in estrogen-deficient rats

This study aims to delineate the relationship among estrogen deficiency, neurodegeneration, and cognitive impairment of ovariectomized rats. Female Sprague-Dawley rats were ovariectomized and euthanized after 1-4 month periods (M(0)-M(4) groups). Blood samples were collected for the determination of serum levels of 17β-estradiol (E(2)), luteinizing hormone (LH), and follicle stimulating hormone (FSH). Five consecutive days before the euthanization, cognitive performance of the rats was examined by Morris water maze test. After euthanization, the hippocampus was collected, and expression of the genes associated with amyloid plaques (App, Adam10 and Bace1) and neurofibrillary tangles (Tau4 and Tau3) were examined by real-time PCR. Serum E(2) levels were declined following 2 weeks of ovariectomy. Conversely, serum FSH and LH levels were profoundly increased by 2 weeks of ovariectomy for approximately 4 and 22 times, respectively. Cognitive impairments, indicated by the longer latency and distance, were observed only in the M(3) and M(4) groups. The Tau4 mRNA levels were significantly increased as early as 1 month after ovariectomy (in the M(1) group; P<0.05), and tended to be increased further with the advancing time. Similarly, the Tau3 mRNA levels were increased by ovariectomy, but with the highest level in the M(1) group, and decreased thereafter. The mRNA levels of App, Adam10 and Bace1 were increased by ovariectomy, but significant differences were observed only in the M(4) group. These results indicate that estrogen deficiency can induce a sequence of events that results in the production of neurofibrillary tangles, amyloid deposition, and spatial memory deficit in rats.