Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
Department of Endocrinology, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, China.
Int J Mol Sci. 2023 Dec 22;25(1):170. doi: 10.3390/ijms25010170.
Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide and has a high incidence in the elderly. Unfortunately, there is no effective therapy for AD owing to its complicated pathogenesis. However, the development of lipid-lowering anti-inflammatory drugs has heralded a new era in the treatment of Alzheimer's disease. Several studies in recent years have shown that lipid metabolic dysregulation and neuroinflammation are associated with the pathogenesis of AD. 3-Hydroxyl 3-methylglutaryl CoA reductase (HMGCR) is a rate-limiting enzyme in cholesterol synthesis that plays a key role in cholesterol metabolism. HMGCR inhibitors, known as statins, have changed from being solely lipid-lowering agents to neuroprotective compounds because of their effects on lipid levels and inflammation. In this review, we first summarize the main regulatory mechanism of HMGCR affecting cholesterol biosynthesis. We also discuss the pathogenesis of AD induced by HMGCR, including disordered lipid metabolism, oxidative stress, inflammation, microglial proliferation, and amyloid-β (Aβ) deposition. Subsequently, we explain the possibility of HMGCR as a potential target for AD treatment. Statins-based AD treatment is an ascent field and currently quite controversial; therefore, we also elaborate on the current application prospects and limitations of statins in AD treatment.
阿尔茨海默病（AD）是全球最常见的神经退行性疾病，在老年人中发病率较高。不幸的是，由于其发病机制复杂，目前尚无有效的 AD 治疗方法。然而，降脂抗炎药物的发展为治疗阿尔茨海默病带来了一个新时代。近年来的几项研究表明，脂代谢失调和神经炎症与 AD 的发病机制有关。3-羟-3-甲基戊二酰辅酶 A 还原酶（HMGCR）是胆固醇合成的限速酶，在胆固醇代谢中起着关键作用。HMGCR 抑制剂，即他汀类药物，由于其对血脂水平和炎症的影响，已从单纯的降脂药物转变为具有神经保护作用的化合物。在这篇综述中，我们首先总结了 HMGCR 影响胆固醇生物合成的主要调节机制。我们还讨论了 HMGCR 诱导 AD 的发病机制，包括脂质代谢紊乱、氧化应激、炎症、小胶质细胞增殖和淀粉样β（Aβ）沉积。随后，我们解释了 HMGCR 作为 AD 治疗潜在靶点的可能性。基于他汀类药物的 AD 治疗是一个新兴领域，目前颇具争议性；因此，我们还详细阐述了他汀类药物在 AD 治疗中的应用前景和局限性。
