The Controversial Role of 24-S-Hydroxycholesterol in Alzheimer's Disease.
The Controversial Role of 24-S-Hydroxycholesterol in Alzheimer's Disease.
复制标题
DOI：
10.3390/antiox10050740
复制
发表时间：
2021-05-07
期刊：
影响因子：
--
通讯作者：
Leonarduzzi G
中科院分区：
文献类型：
--
作者：
Gamba P;Giannelli S;Staurenghi E;Testa G;Sottero B;Biasi F;Poli G;Leonarduzzi G
阿尔茨海默病(AD)的发生发展受多种因素的影响，其中脑内胆固醇代谢紊乱起主要作用。维持脑内胆固醇的稳态对神经元功能和大脑发育至关重要。为了保持稳态水平，过量的大脑胆固醇被神经元特异性酶CYP46A1转化为更亲水的代谢物24-S-羟基胆固醇(24-OHC)，也被称为脑固醇。越来越多的证据表明，胆固醇氧化产物，即氧化甾醇，是连接胆固醇代谢变化和AD的纽带。已有研究表明，阿尔茨海默病患者大脑中的27-羟基胆固醇、7-β-羟基胆固醇和7-酮胆固醇等氧固醇水平显著升高，导致疾病进展。相反，24-OHC水平下降，可能是由于神经元丢失。在不同的大脑氧化甾醇中，24-OHC的作用肯定是最有争议的。它是大脑中占主导地位的氧固醇，有证据表明，它代表着一种对大脑功能非常重要的信号分子。然而，许多研究强调了24-OHC在促进AD发展中的潜在作用，因为它促进了神经炎症、淀粉样蛋白β(Aβ)肽的产生、氧化应激和细胞死亡。同时，24-OHC已被证明对AD进展有几个有益的作用，例如防止tau过度磷酸化和Aβ的产生。本文就24-OHC在AD发病机制中有争议的作用进行综述，对不同AD生物样品中24-OHC的水平及其在脑内的毒性或神经保护作用进行了详细的综述。鉴于24-OHC在AD病理生理学中的相关作用，它的靶向性可能有助于疾病预防或减缓其进展。
The development of Alzheimer’s disease (AD) is influenced by several events, among which the dysregulation of cholesterol metabolism in the brain plays a major role. Maintenance of brain cholesterol homeostasis is essential for neuronal functioning and brain development. To maintain the steady-state level, excess brain cholesterol is converted into the more hydrophilic metabolite 24-S-hydroxycholesterol (24-OHC), also called cerebrosterol, by the neuron-specific enzyme CYP46A1. A growing bulk of evidence suggests that cholesterol oxidation products, named oxysterols, are the link connecting altered cholesterol metabolism to AD. It has been shown that the levels of some oxysterols, including 27-hydroxycholesterol, 7β-hydroxycholesterol and 7-ketocholesterol, significantly increase in AD brains contributing to disease progression. In contrast, 24-OHC levels decrease, likely due to neuronal loss. Among the different brain oxysterols, 24-OHC is certainly the one whose role is most controversial. It is the dominant oxysterol in the brain and evidence shows that it represents a signaling molecule of great importance for brain function. However, numerous studies highlighted the potential role of 24-OHC in favoring AD development, since it promotes neuroinflammation, amyloid β (Aβ) peptide production, oxidative stress and cell death. In parallel, 24-OHC has been shown to exert several beneficial effects against AD progression, such as preventing tau hyperphosphorylation and Aβ production. In this review we focus on the current knowledge of the controversial role of 24-OHC in AD pathogenesis, reporting a detailed overview of the findings about its levels in different AD biological samples and its noxious or neuroprotective effects in the brain. Given the relevant role of 24-OHC in AD pathophysiology, its targeting could be useful for disease prevention or slowing down its progression.
登录
查看更多内容
影响因子：
14.5
作者：
Djelti, Fathia;Braudeau, Jerome;Cartier, Nathalie
通讯作者：
Cartier, Nathalie
影响因子：
9.9
作者：
Cramer, C.;Haan, M. N.;Kalbfleisch, J. D.
通讯作者：
Kalbfleisch, J. D.
影响因子：
4.7
作者：
Collingridge GL;Volianskis A;Bannister N;France G;Hanna L;Mercier M;Tidball P;Fang G;Irvine MW;Costa BM;Monaghan DT;Bortolotto ZA;Molnár E;Lodge D;Jane DE
通讯作者：
Jane DE
影响因子：
34.7
作者：
Bu, Guojun
通讯作者：
Bu, Guojun
影响因子：
2.5
作者：
Besga, A.;Cedazo-Minguez, A.;Wahlund, L. O.
通讯作者：
Wahlund, L. O.