Androgens protect against apolipoprotein E4-induced cognitive deficits - PubMed (original) (raw)

Androgens protect against apolipoprotein E4-induced cognitive deficits

Jacob Raber et al. J Neurosci. 2002.

Abstract

Compared with apolipoprotein (apo) E2 and E3, apoE4 increases the risk of Alzheimer's disease (AD), but it remains unknown how apoE4 affects neuronal function. ApoE4 interacts with female gender, further increasing the risk of AD and decreasing treatment response. Female mice are also more susceptible to apoE4-induced impairments of spatial learning and memory than male mice. To assess the role of sex steroids in this process, we studied mice deficient in mouse apoE (Apoe(-/-)) and expressing human apoE4 or apoE3 in the brain at comparable levels. Even brief periods of androgen treatment improved the memory deficits of female apoE4 mice. Female apoE3 mice had no memory deficits and did not benefit from the treatment. ApoE4 male mice, which performed normally in a water-maze test at baseline, developed prominent deficits in spatial learning and memory after blockade of androgen receptors (ARs), whereas apoE3 male mice did not. Untreated apoE4 mice had significantly lower cytosolic AR levels in the neocortex than wild-type, Apoe(-/-), and apoE3 mice. Improved memory in androgen-treated female apoE4 mice was associated with increased cytosolic AR levels. Our findings suggest that apoE4 contributes to cognitive decline by reducing AR levels in the brain, and that stimulating AR-dependent pathways can reverse apoE4-induced cognitive deficits.

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Figures

Fig. 1.

Fig. 1.

ApoE4-induced deficits in spatial learning and memory can be improved by stimulating ARs. Six-month-old female NSE–apoE4 and NSE–apoE3 mice were tested in the water maze beginning 8 d after the subcutaneous implantation of testosterone, dihydrotestosterone, or placebo capsules (n = 5–11 mice per genotype and treatment). After the behavioral testing, plasma hormone levels were determined by radioimmunoassay to ensure the effectiveness of the implants (see Results). A, Testosterone improved spatial learning in female apoE4 mice. Although all three groups learned to locate the hidden platform, there was a significant difference between the learning curves of testosterone- and placebo-treated mice during the hidden-platform sessions (p < 0.05; repeated-measures ANOVA).B, In the probe trial (platform removed), both testosterone- and dihydrotestosterone-treated apoE4 mice, but not placebo-treated apoE4 mice, spent significantly more time searching in the target quadrant than in any of the other quadrants (*p < 0.05; Tukey–Kramer test). However, the dihydrotestosterone effect was relatively weak. Although the ratio of mice spending ≥35% versus <35% in the target quadrant was higher after testosterone (5:0) than after placebo (1:4) treatment (p < 0.01; χ2 test), it did not differ significantly from placebo after dihydrotestosterone treatment (5:4; p = 0.2; χ2 test). Learning curves calculated from distance moved were similar to those calculated from latencies (data not shown). C, D, Testosterone did not improve spatial learning and memory in female apoE3 mice. *p < 0.05 versus any other quadrant (Tukey–Kramer test). E, F, Trials 1–3 of the first hidden-platform session. Latency values for each session (A, C) represent the averages from three consecutive trials. Comparison of latencies in each of the first three hidden-platform trials by ANOVA revealed a significant interaction between treatment and genotype during trials 2 (p = 0.002) and 3 (p = 0.027) but not trial 1 (p = 0.95). Comparison of the four learning curves by repeated-measures ANOVA also identified a significant interaction between treatment and genotype (p = 0.028). Moreover, the effect of genotype was significant only in the placebo-treated groups (p = 0.002) but not in the testosterone-treated groups (p = 0.93).

Fig. 2.

Fig. 2.

Blockade of ARs impaired spatial learning and memory in male apoE4 but not apoE3 mice. Six-month-old male NSE–apoE4 and NSE–apoE3 mice (n = 6–7 mice per genotype and treatment) were tested in the water maze during AR blockade with hydroxyflutamide (see Materials and Methods). A, Hydroxyflutamide impaired learning in the hidden-platform sessions in apoE4 mice (p < 0.05 vs vehicle-treated apoE4 mice; repeated-measures ANOVA) but not in apoE3 mice.B, Hydroxyflutamide impaired retention of spatial memory in apoE4 but not apoE3 mice. *p < 0.05 versus any other quadrant (Tukey–Kramer test).

Fig. 3.

Fig. 3.

ApoE4 impairs object-recognition memory in female mice. Novel-object recognition was tested in untreated 6-month-old male (M) and female (F) mice. The results shown are from the memory-retention session.A, NSE–apoE4 (11 males, 7 females) and NSE–apoE3 (4 males, 7 females) mice. B, Wild-type (Wt) (11 males, 6 females) and Apoe −/− (7 males, 13 females) mice. C,Apoe−/− (6 females) and GFAP–apoE4 (6 females) mice. Most mice showed normal object-recognition memory. Only female mice that expressed apoE4 in neurons (A) or astrocytes (C) failed to spend significantly more time with the novel than with the familiar object. °p < 0.05; *p < 0.01 versus time exploring the familiar object (Tukey–Kramer test); n.s., not significant.

Fig. 4.

Fig. 4.

Cytosolic AR levels in the neocortex and response to androgen treatment. Total cytosolic AR levels were determined from AR saturation curves using a single curve-fit analysis. Results are expressed as femtomoles of [3H]R1881 bound per milligram of protein. There were no differences in_K_d among the groups (data not shown).A, Untreated male and female NSE–apoE4 mice had lower cytosolic AR levels than untreated NSE–apoE3,Apoe −/−, and wild-type (Wt) mice (n = 3–7 mice per gender and genotype). B–D, Effect of placebo (B), testosterone (C), and dihydrotestosterone (D) on AR saturation curves in female NSE–apoE4 mice (n = 3–6 mice per treatment).

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