Tfm-AR modulates the effects of ApoE4 on cognition.

Female mice are more susceptible to apolipoprotein E (apoE4)-induced cognitive deficits than male mice. These deficits can be antagonized by stimulating androgen receptors (ARs). To determine the role of AR in the cognitive effects of apoE4, we backcrossed mutant mice with a naturally occurring defect in the AR [testicular feminization mutant (tfm)] onto the Apoe-/- background to eliminate mouse apoE gene resulting in non-functional AR, and crossed the tfm/Apoe-/- female mice with apoE4 transgenic male mice. We behaviorally compared Apoe-/-, apoE4, tfm, and tfm/apoE4 male mice. Apoe-/-, apoE4, and tfm mice showed hippocampus-dependent novel location recognition but tfm/apoE4 mice did not. In contrast, all groups showed hippocampus-independent novel object recognition. Hippocampus-dependent learning and memory were also assessed in the water maze. In the water maze probe trial following the second day of hidden platform training, Apoe-/- and apoE4 mice showed spatial memory retention, but tfm and tfm/ApoE4 mice did not. In the water maze, probe trial following the third day of hidden platform training, Apoe-/-, apoE4, and tfm/Apoe-/- mice showed spatial memory retention, but tfm mice did not. These data support an important role for AR in protecting against the detrimental effects of apoE4 on hippocampus-dependent learning and memory.