Research ReportRole of circulating androgen levels in effects of apoE4 on cognitive function
Introduction
Distinct alleles (ε2, ε3, and ε4) encode the major human apolipoprotein (apo) E isoforms, which play important roles in the metabolism and redistribution of lipoproteins and cholesterol [23]. The three major human apoE isoforms, ε2, ε3, and ε4, are encoded by distinct alleles. In the brain, apoE has been implicated in development, regeneration, neurite outgrowth, and neuroprotection [4], [23], [28], [29], [30], [32], [39]. In addition, apoE has been implicated in the synthesis of glucocorticoids and sex hormones [42], [43], [44]. Compared with ε2 and ε3, ε4 increases the risk of cognitive impairments and of developing Alzheimer's disease (AD) [6]. Female sex is a risk factor for AD and apoE4 interacts with female sex, resulting in an even greater AD [41]. Consistent with these human data, adult apoE4 transgenic female, but not male, mice lacking mouse apoE (Apoe−/−) show impairments in object recognition and spatial learning and memory in the water maze [31], [33], [34].
Sex steroids, which cause sex differences in brain organization and affect cognitive performance in adulthood, might contribute to the sexually dimorphic performance in learning and memory. Androgens have been shown to modulate hippocampal-dependent behavior, including learning and memory; testosterone enhanced spatial learning and memory [7], [19], [34], [35], [36] and both short-term and long-term emotional learning and memory [40]. In addition, post-training administration of androgens to ovariectomized rats enhanced spatial and emotional learning and memory temporally [8]. Finally, androgens modulated the expression of the immediate early gene c-fos in the hippocampus following exposure to a novel open field [21]. However, in some studies, androgens impaired spatial learning and memory [9], [12], [13], [14] and administration of testosterone in the CA1 of the hippocampus [26] or the basolateral amygdala [27], brain areas with a high concentration of androgen receptors [18], [38], impaired spatial learning and memory.
Androgens and androgen receptor-mediated signaling might protect against the detrimental effects of apoE4 on cognitive function. Brief periods of androgen treatment antagonized cognitive deficits in adult apoE4 female mice and acute AR blockade with hydroxyflutamide caused striking cognitive impairments in apoE4, but not apoE3, male mice [34]. In addition, expression of apoE4, but not apoE3, significantly reduced cytosolic AR binding in the neocortex compared to Apoe−/− mice. The lower circulating concentrations of endogenous androgens in females than males might contribute to their increased susceptibility to the detrimental effects of apoE4 on AR binding and cognitive function. To test this hypothesis, in the present study, we explored the influence of chronic reduced circulating androgens on the cognitive performance of human apoE transgenic male mice.
Section snippets
Mice
The generation and genotyping of neuron-specific enolase (NSE)-apoE male mice have been described previously [31], [32], [33], [34]. The Apoe−/− mice used in this study were littermate controls. To minimize the effects of social influences on behavior, 6–7-month-old mice (n = 45) were housed singly starting 1 week before behavioral testing under conditions of constant temperature (18°C), and light from 6:00 a.m. to 6:00 p.m. All mice had free access to food (PicoLab Rodent Diet 20, #5053, PMI
Plasma Testosterone
To determine the effectiveness of the castration, plasma testosterone levels were verified in 12 mice (Apoe−/−: n = 6; apoE3: n = 3; apoE4: n = 3) following behavioral testing. In 7 mice, plasma testosterone levels were below the detection level. The levels in the remaining mice were 0.65 and 0.19 ng/ml (Apoe−/−), 0.22 ng/ml (apoE3), and 0.12 and 0.50 ng/ml (apoE4), confirming that the castration was effective.
Open field and rotorod
Six–seven-month-old castrated and sham-castrated male Apoe−/−, apoE3, and apoE4 mice (
Discussion
This study shows that castration impaired novel location recognition in apoE4, but not apoE3 or Apoe−/−, mice. In contrast, castration impaired novel object recognition and spatial memory retention in the water maze in Apoe−/−, but not apoE3 or apoE4, mice. In the water maze, castrated, but not sham-castrated, apoE4 mice showed improved acquisition over the first two hidden platform sessions and spatial memory retention in the first probe trial. ApoE3 and Apoe−/−, but not apoE4, mice showed
Acknowledgments
This work was supported by NIH AG20904 and EMF AG-NS-0201.
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