Taipei Neuroscience Institute, Taipei Medical University, Taipei 110, Taiwan.
Chi Mei Medical Center, Tainan 71004, Taiwan.
J Steroid Biochem Mol Biol. 2024 Oct;243:106585. doi: 10.1016/j.jsbmb.2024.106585. Epub 2024 Jul 15.
Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss. Recent studies have suggested a potential role for steroid synthesis in AD pathology. This study investigated the co-localization of steroidogenic enzymes in neuronal cells, changes in enzyme expression in an AD mouse model, and steroid expressions in human AD samples. Additionally, we conducted a steroidomic metabolomics analysis and evaluated the effects of dehydroepiandrosterone sulfate (DHEAS) treatment in an AD mouse model. Immunofluorescence analysis revealed significant co-localization of cytochrome P450 family 17 subfamily A member 1 (CYP17A1) and steroidogenic acute regulatory protein (StAR) proteins with α-synuclein in presynaptic neurons, suggesting active steroid synthesis in these cells. Conversely, such co-localization was absent in astrocytes. In the AD mouse model, a marked decrease in the expression of steroidogenic enzymes (Cyp11a1, Cyp17a1, Star) was observed, especially in areas with amyloid beta plaque accumulation. Human AD and MS brain tissues showed similar reductions in StAR and CYP17A1 expressions. Steroidomic analysis indicated a downregulation of key steroids in the serum of AD patients. DHEAS treatment in AD mice resulted in improved cognitive function and reduced Aβ accumulation. Our findings indicate a neuron-specific pathway for steroid synthesis, potentially playing a crucial role in AD pathology. The reduction in steroidogenic enzymes and key steroids in AD models and human samples suggests that impaired steroid synthesis is a feature of neurodegenerative diseases. The therapeutic potential of targeting steroid synthesis pathways, as indicated by the positive effects of DHEAS treatment, warrants further investigation.
阿尔茨海默病（AD）是一种以认知能力下降和记忆丧失为特征的神经退行性疾病。最近的研究表明，类固醇合成在 AD 病理中可能具有潜在作用。本研究调查了神经元细胞中类固醇生成酶的共定位、AD 小鼠模型中酶表达的变化以及人类 AD 样本中的类固醇表达。此外，我们进行了类固醇代谢组学分析，并评估了 DHEAS 在 AD 小鼠模型中的治疗效果。免疫荧光分析显示，细胞色素 P450 家族 17 亚家族 A 成员 1（CYP17A1）和类固醇生成急性调节蛋白（StAR）蛋白与突触前神经元中的α-突触核蛋白有显著的共定位，表明这些细胞中存在活跃的类固醇合成。相反，星形胶质细胞中没有这种共定位。在 AD 小鼠模型中，观察到类固醇生成酶（Cyp11a1、Cyp17a1、Star）的表达显著下降，特别是在淀粉样β斑块积累的区域。人类 AD 和 MS 脑组织显示 StAR 和 CYP17A1 表达相似减少。类固醇组学分析表明 AD 患者血清中的关键类固醇下调。DHEAS 在 AD 小鼠中的治疗导致认知功能改善和 Aβ 积累减少。我们的研究结果表明存在一种神经元特异性的类固醇合成途径，可能在 AD 病理中发挥关键作用。AD 模型和人类样本中类固醇生成酶和关键类固醇的减少表明，类固醇合成受损是神经退行性疾病的一个特征。靶向类固醇合成途径的治疗潜力，如 DHEAS 治疗的积极效果所示，值得进一步研究。
