Gamba Paola, Giannelli Serena, Staurenghi Erica, Testa Gabriella, Sottero Barbara, Biasi Fiorella, Poli Giuseppe, Leonarduzzi Gabriella
Department of Clinical and Biological Sciences, University of Turin, 10043 Turin, Italy.
Antioxidants (Basel). 2021 May 7;10(5):740. doi: 10.3390/antiox10050740.
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.
阿尔茨海默病（AD）的发展受到多种因素的影响，其中大脑中胆固醇代谢失调起着主要作用。维持大脑胆固醇稳态对于神经元功能和大脑发育至关重要。为维持稳态水平，过量的大脑胆固醇通过神经元特异性酶CYP46A1转化为亲水性更强的代谢产物24-S-羟基胆固醇（24-OHC），也称为脑甾醇。越来越多的证据表明，胆固醇氧化产物，即氧化甾醇，是将胆固醇代谢改变与AD联系起来的纽带。研究表明，包括27-羟基胆固醇、7β-羟基胆固醇和7-酮胆固醇在内的一些氧化甾醇水平在AD大脑中显著升高，促进了疾病进展。相比之下，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的作用无疑最具争议性。它是大脑中占主导地位的氧化甾醇，并表明它是对大脑功能非常重要的信号分子。然而，大量研究强调了24-OHC在促进AD发展方面的潜在作用，因为它会促进神经炎症、淀粉样β（Aβ）肽生成、氧化应激和细胞死亡。同时，已证明24-OHC对AD进展具有多种有益作用，如预防tau过度磷酸化和Aβ生成。在本综述中，我们聚焦于24-OHC在AD发病机制中争议性作用的当前知识，详细概述了其在不同AD生物样本中的水平以及在大脑中的有害或神经保护作用的研究结果。鉴于24-OHC在AD病理生理学中的相关作用，针对它可能有助于疾病预防或减缓其进展。
