CYP46A1-mediated cholesterol turnover induces sex-specific changes in cognition and counteracts memory loss in ovariectomized mice.
CYP46A1-mediated cholesterol turnover induces sex-specific changes in cognition and counteracts memory loss in ovariectomized mice.
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DOI：
10.1126/sciadv.adj1354
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发表时间：
2024-01-26
期刊：
影响因子：
13.6
通讯作者：
Maioli, Silvia
中科院分区：
文献类型：
--
作者：
Latorre-Leal, Maria;Rodriguez-Rodriguez, Patricia;Franchini, Luca;Nikolidakis, Orestis;Daniilidou, Makrina;Delac, Ljerka;Varshney, Mukesh K.;Arroyo-Garcia, Luis E.;Eroli, Francesca;Winblad, Bengt;Blennow, Kaj;Zetterberg, Henrik;Kivipelto, Miia;Pacciarini, Manuela;Wang, Yuqin;Griffiths, William J.;Bjoerkhem, Ingemar;Matton, Anna;Nalvarte, Ivan;Merino-Serrais, Paula;Cedazo-Minguez, Angel;Maioli, Silvia
脑特异性酶CYP 46 A1通过将胆固醇转化为24 S-羟基胆固醇（24 OH）来控制胆固醇周转。在阿尔茨海默病（AD）中观察到脑胆固醇转换的失调和降低的CYP 46 A1水平。在这项研究中，我们报告说，CYP 46 A1在老年雌性小鼠中的过表达导致海马中雌激素信号的增强和认知功能的改善。相比之下，年龄匹配的CYP 46 A1过表达男性显示焦虑样行为、记忆力下降和海马体中5α-二氢睾酮水平升高。我们报告说，在神经元中，24 OH通过激活性激素信号，包括雌激素受体，促进这些不同的影响。CYP 46 A1在雌性小鼠中的过表达可以保护卵巢切除术诱导的记忆障碍，而在性腺切除的雄性小鼠中没有影响。最后，我们测量了AD患者临床队列的脑脊液24 OH水平，发现仅在女性中24 OH与神经退行性标志物呈负相关。我们认为，CYP 46 A1激活是一个有价值的药理学目标，增强雌激素信号的妇女在发展神经退行性疾病的风险。CYP 46 A1过表达在雌性小鼠的时间和内分泌衰老过程中具有神经保护作用。
The brain-specific enzyme CYP46A1 controls cholesterol turnover by converting cholesterol into 24S-hydroxycholesterol (24OH). Dysregulation of brain cholesterol turnover and reduced CYP46A1 levels are observed in Alzheimer’s disease (AD). In this study, we report that CYP46A1 overexpression in aged female mice leads to enhanced estrogen signaling in the hippocampus and improved cognitive functions. In contrast, age-matched CYP46A1 overexpressing males show anxiety-like behavior, worsened memory, and elevated levels of 5α-dihydrotestosterone in the hippocampus. We report that, in neurons, 24OH contributes to these divergent effects by activating sex hormone signaling, including estrogen receptors. CYP46A1 overexpression in female mice protects from memory impairments induced by ovariectomy while having no effects in gonadectomized males. Last, we measured cerebrospinal fluid levels of 24OH in a clinical cohort of patients with AD and found that 24OH negatively correlates with neurodegeneration markers only in women. We suggest that CYP46A1 activation is a valuable pharmacological target for enhancing estrogen signaling in women at risk of developing neurodegenerative diseases. CYP46A1 overexpression is neuroprotective in female mice during chronological and endocrine aging.
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影响因子：
3.5
作者：
Frankfurt M;Luine V
通讯作者：
Luine V
影响因子：
3.6
作者：
Gen, K;Okuzawa, K;Kagawa, H
通讯作者：
Kagawa, H
影响因子：
4.2
作者：
Boros BD;Greathouse KM;Gearing M;Herskowitz JH
通讯作者：
Herskowitz JH
影响因子：
2.9
作者：
Nguyen TV;Yao M;Pike CJ
通讯作者：
Pike CJ
DOI：
10.3390/antiox10050740
发表时间：
2021-05-07
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
--
作者：
Gamba P;Giannelli S;Staurenghi E;Testa G;Sottero B;Biasi F;Poli G;Leonarduzzi G
通讯作者：
Leonarduzzi G