COMBINING FUNCTIONAL IMAGING WITH MICROARRAY: THE TRANSCRIPTIONAL-SILENCER RBAP48 IS IMPLICATED IN COGNITIVE AGING

K.A. Kent¹; A. Pierce¹; F.P. Houston²; C. Leung¹;
T. Kim¹; L. Honig¹; J. Vonsattel¹; C.A. Barnes²;
S.A. Small¹*

1. Columbia Univ, New York, NY, USA
2. NSMA, Univ Arizona, Tucson, AZ, USA

Imaging studies in humans, monkeys, and rats have established that: a) the dentate gyrus is the hippocampal subregion most vulnerable to the effects of normal aging; b) the function of the dentate gyrus declines linearly across the life span; and, c) the entorhinal cortex is the hippocampal subregion most resistant to aging. Based on these imaging findings, a hypothesis-driven model was constructed on how a molecule underlying cognitive aging should behave - spatially and over time. The dentate gyrus and the entorhinal cortex were harvested from healthy human brains (33-81 yrs), and microarray analysis was used to establish gene-expression profiles from each sample. In accordance with the spatiotemporal model, a partial correlation analysis was performed for each transcript, where age and dentate gyrus expression were included as primary variables, and entorhinal expression was included as a covariate (designed to factor out individual sources of noise, i.e., genetics, environment and variables related to the dying process). Age-related decline in the expression of RbAp48, a WD-40 molecule that regulates transcriptional silencing, best conformed to the spatiotemporal model (p = 0.0004). Next, we used Western blot analysis to determine RbAp48 expression in the dentate gyrus and entorhinal cortex harvested from behaviorally-characterized rats, ranging from 7-27 months of age. The same spatiotemporal pattern of decline uncovered in humans was found in rats. More importantly, RbAp48 expression in the old rats correlated with memory performance (p = 0.02), thus confirming its relevance to age-related memory decline. Taken together, an unexplored molecular pathway has been isolated that can account for cognitive aging.

Support Contributed By: AG09219, AG03376, RR-000169, AG08702, AG00949, Beeson Award, & McKnight fund