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通过CYP46A1调节的胆固醇周转会会诱导性别特异性的认知变化,并抵消卵巢切除小鼠的记忆丧失

María Latorre-Leal¹, Patricia Rodriguez-Rodriguez¹, Luca Franchini¹

¹Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden.

Science advances

|January 24, 2024

概括

激活CYP46A1酶增强雌激素信号传递,改善雌性小鼠的认知能力,为女性的阿尔茨海默氏症等神经退行性疾病提供潜在的治疗点.

科学领域:

神经生物学神经生物学神经生物学
内分泌学在内分泌学.
胆固醇的新陈代谢

背景情况:

特定于大脑的酶CYP46A1通过产生24S-基胆固醇 (24OH) 来调节胆固醇的循环.
改变胆固醇代谢和减少CYP46A1表达与阿尔茨海默病 (AD) 有关.
性激素显著影响大脑功能和神经保护.

研究的目的:

研究CYP46A1过度表达对老年小鼠认知功能和性激素信号传递的影响.
探索24OH在调解CYP46A1.1.的性别特异性影响中的作用.
为了检查24OH水平和神经退行症标志物在人类AD患者之间的相关性.

主要方法:

在老年雄性和雌性小鼠中过度表达CYP46A1.
评估认知功能,类似焦虑的行为和海马体性激素水平.
对AD患者的脑脊液 (CSF) 进行24OH和神经退行症标志物的分析.

主要成果:

过度表达CYP46A1在雌性小鼠中增强了雌激素信号传递和认知功能,但在雄性小鼠中引起了焦虑和记忆缺陷.
24OH激活了神经元中的性激素信号通路,包括雌激素受体,调解了这些不同的效应.
过度表达CYP46A1保护了被切除卵巢的女性免受记忆障碍,但对被切除卵巢的男性没有影响.
在人类AD患者中,24OH水平与神经退行症标志物负相关,仅在女性中.

结论:

激活CYP46A1对大脑功能和行为产生差异性影响,以特定性别的方式,由24OH介导.
通过CYP46A1激活来增强雌激素信号传递,显示出对有神经退行性疾病风险的妇女的治疗潜力.
作为治疗神经退行性疾病的有前途的药理目标,CYP46A1特别适用于女性.

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