The Influence of Estrogen on a Potential Memory Gene, RbAp48

Purpose: With aging, there is a tendency for humans to experience cognitive decline. Known variations in cognitive function with age provide an opportunity to investigate the reasons why some individuals age successfully while others do not. In some women, the postmenopausal period is associated with a decline in cognitive function. While hormone (replacement) therapy may have merit, its current use for treating cognitive dysfunction is controversial. At best, we recognize that there are responders and non-responders. Given that the histone binding protein, RbAp48, was recently implicated as a key determinant of cognitive dysfunction with age, we sought to determine the role of RbAp48 as a mediator of estrogen’s influence on cognitive function. As an initial investigation into the role of RbAp48 in mediating estrogen’s effect on cognitive function, we sought to determine if, in animal models of aging currently being used in our laboratory, RbAp48 declines with age, and if estrogen treatment influences RbAp48 expression. Methods: We evaluated the expression of RbAp48 in the hippocampus of female Sprague Dawley rats that were 4 months and 10 months of age, representing young adult and middle-aged rats. Within these two groups, we had two treatment groups: ovariectomized (OVX) and ovariectomized + estradiol treatment (OVX + E2). RbAp48 mRNA was assessed using semi-quantitative real-time PCR (rtPCR). GAPDH was used as a loading control, as it is stably expressed at high levels. Differences in expression of RbAp48 were based on the delta-delta CT methodology published by Livak and Schmittgen (2001). Statistical evaluation of differences between experimental groups was determined using a two-tailed t-test. Results: Our data revealed a statistically significant (n=5, p=0.0079) reduction in the levels of hippocampal RbAp48 mRNA in the 10 month mice, compared to the 4 month mice. Interestingly, E2 reduced RbAp48 in young OVX rats (n=5, p=0.0079), but had no effect on RbAp48 mRNA levels in middle-aged ovariectomized (n=5, p=0.1508). Conclusions: These studies confirm the reduction of RbAp48, a presumptive “memory gene”, with with age, but failed to implicate RbAp48 as a mediator of E2’s effects. Instead, we suggest that RbAp48 is permissive for E2’s effects. Ongoing studies will determine whether knockdown of RbAp48 expression abrogates estrogen’s positive effects on those measures relevant to cognitive function.