Androgens protect against apolipoprotein E4-induced cognitive deficits
Androgens protect against apolipoprotein E4-induced cognitive deficits
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DOI：
10.1523/jneurosci.22-12-05204.2002
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发表时间：
2002-06-15
影响因子：
5.3
通讯作者：
Mucke, L
中科院分区：
文献类型：
--
作者：
Raber, J;Bongers, G;Mucke, L
与载脂蛋白（apo）E2和E3相比，apoE4会增加患阿尔茨海默病（AD）的风险，但apoE4如何影响神经元功能仍不清楚。 ApoE4 与女性相互作用，进一步增加 AD 风险并降低治疗反应。与雄性小鼠相比，雌性小鼠也更容易受到 apoE4 诱导的空间学习和记忆障碍的影响。为了评估性类固醇在这一过程中的作用，我们研究了缺乏小鼠 apoE (Apoe(-/-)) 并在大脑中以相当水平表达人类 apoE4 或 apoE3 的小鼠。即使是短暂的雄激素治疗也能改善雌性 apoE4 小鼠的记忆缺陷。雌性 apoE3 小鼠没有记忆缺陷，也没有从治疗中受益。 ApoE4 雄性小鼠在基线水迷宫测试中表现正常，但在雄激素受体 (AR) 阻断后，在空间学习和记忆方面出现了明显的缺陷，而 apoE3 雄性小鼠则没有。未经治疗的 apoE4 小鼠新皮质中的胞质 AR 水平显着低于野生型、Apoe(-/-) 和 apoE3 小鼠。雄激素治疗的雌性 apoE4 小鼠记忆力的改善与胞质 AR 水平的增加有关。我们的研究结果表明，apoE4 通过降低大脑中的 AR 水平而导致认知能力下降，并且刺激 AR 依赖性通路可以逆转 apoE4 引起的认知缺陷。
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.