Alzheimer’s disease (AD) is a progressive neurological disorder that impairs memory and cognitive abilities, primarily in the elderly. The burden of AD extends beyond patients, impacting families and caregivers due to the patients’ reliance on assistance for daily tasks. The main features of the pathogenesis of AD are beta-amyloid plaques and neurofibrillary tangles (NFTs), that strongly correlate with oxidative stress and inflammation. NFTs result from misfolded and hyperphosphorylated tau proteins. Various studies have focused on tau phosphorylation, indicating protein phosphatase 2A (PP2A) as the primary tau phosphatase and glycogen synthase kinase-3 beta (GSK-3β) as the leading tau kinase. Experimental evidence suggests that inhibition of PP2A and increased GSK-3β activity contribute to neuroinflammation, oxidative stress, and cognitive impairment. Hence, targeting PP2A and GSK-3β with pharmacological approaches shows promise in treating AD. The use of natural compounds in the drug development for AD have been extensively studied for their antioxidant, anti-inflammatory, anti-cholinesterase, and neuroprotective properties, demonstrating therapeutic advantages in neurological diseases. Alongside the development of PP2A activator and GSK-3β inhibitor drugs, natural compounds are likely to have neuroprotective effects by increasing PP2A activity and decreasing GSK-3β levels. Therefore, based on the preclinical and clinical studies, the potential of PP2A and GSK-3β as therapeutic targets of natural compounds are highlighted in this review.

中文翻译：

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天然化合物能否靶向蛋白磷酸酶 2A 和糖原合酶激酶 3 beta 来改善阿尔茨海默病病理？

阿尔茨海默病 (AD) 是一种进行性神经系统疾病，会损害记忆和认知能力，尤其是老年人。 AD 的负担超出了患者的范围​​，由于患者依赖援助来完成日常任务，因此影响了家庭和护理人员。 AD 发病机制的主要特征是 β-淀粉样斑块和神经原纤维缠结 (NFT)，它们与氧化应激和炎症密切相关。 NFT 由错误折叠和过度磷酸化的 tau 蛋白产生。各种研究都集中在 tau 磷酸化上，表明蛋白磷酸酶 2A (PP2A) 是主要的 tau 磷酸酶，糖原合酶激酶 3 beta (GSK-3β) 是主要的 tau 激酶。实验证据表明，抑制 PP2A 和增加 GSK-3β 活性会导致神经炎症、氧化应激和认知障碍。因此，通过药理学方法靶向 PP2A 和 GSK-3β 在治疗 AD 方面显示出希望。天然化合物在 AD 药物开发中的应用因其抗氧化、抗炎、抗胆碱酯酶和神经保护特性而得到广泛研究，证明了其在神经系统疾病中的治疗优势。随着 PP2A 激活剂和 GSK-3β 抑制剂药物的开发，天然化合物可能通过增加 PP2A 活性和降低 GSK-3β 水平而具有神经保护作用。因此，基于临床前和临床研究，本综述强调了 PP2A 和 GSK-3β 作为天然化合物治疗靶点的潜力。