School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan.
Department of Orthopedics, Chung Shan Medical University Hospital, Taichung 402, Taiwan.
Int J Mol Sci. 2024 Nov 12;25(22):12114. doi: 10.3390/ijms252212114.
Dementia with Lewy bodies (DLB) is a progressive neurodegenerative disorder marked by the accumulation of α-synuclein (αSyn), often co-existing with amyloid β (Aβ) pathology. Current treatments are largely symptomatic, highlighting a critical need for disease-modifying therapies. Evidence suggests that αSyn aggregates contribute to neuronal death in DLB, particularly when exacerbated by Aβ. Given the role of autophagy in clearing misfolded proteins, exploring agents that promote this pathway is essential for developing effective treatments. Ambroxol (AMBX), a mucolytic drug, has demonstrated potential in activating glucocerebrosidase (GCase), an enzyme that enhances lysosomal function and facilitates the autophagic clearance of toxic protein aggregates, including αSyn. This study aims to evaluate AMBX's neuroprotective effects in a cellular model of DLB, with the goal of identifying new therapeutic agents that target the underlying pathology of DLB. In this study, HT-22 hippocampal neuronal cells were exposed to αSyn and Aβ, followed by AMBX treatment. Our results showed that AMBX significantly improved cell viability and reduced apoptosis in cells co-treated with αSyn and Aβ. Additionally, AMBX restored GCase activity, promoted autophagy, and reduced oxidative stress, which in turn mitigated αSyn aggregation and phosphorylation. These findings suggest that by activating GCase and enhancing autophagy, AMBX may help alleviate DLB-associated neurodegeneration. This study underscores the potential of AMBX as a therapeutic agent for DLB and supports further investigation in animal models and clinical trials to validate its efficacy in neurodegenerative disease contexts.
路易体痴呆症（DLB）是一种进行性神经退行性疾病，其特征是α-突触核蛋白（αSyn）的积累，通常与淀粉样β（Aβ）病理学共存。目前的治疗方法主要是对症治疗，突出了对疾病修饰疗法的迫切需求。有证据表明，αSyn 聚集体在 DLB 中导致神经元死亡，尤其是在被 Aβ 加剧时。鉴于自噬在清除错误折叠的蛋白质中的作用，探索促进该途径的药物对于开发有效的治疗方法至关重要。氨溴索（AMBX）是一种黏液溶解药物，已被证明具有激活葡萄糖脑苷脂酶（GCase）的潜力，该酶增强溶酶体功能并促进有毒蛋白聚集体（包括 αSyn）的自噬清除。本研究旨在评估 AMBX 在 DLB 细胞模型中的神经保护作用，目的是确定新的治疗剂，以靶向 DLB 的潜在病理学。在这项研究中，HT-22 海马神经元细胞暴露于 αSyn 和 Aβ 后，用 AMBX 进行处理。我们的研究结果表明，AMBX 显著提高了共处理 αSyn 和 Aβ 的细胞活力并降低了细胞凋亡。此外，AMBX 恢复了 GCase 活性，促进了自噬，并减少了氧化应激，从而减轻了 αSyn 聚集和磷酸化。这些发现表明，通过激活 GCase 和增强自噬，AMBX 可能有助于缓解与 DLB 相关的神经退行性变。本研究强调了 AMBX 作为 DLB 治疗剂的潜力，并支持在动物模型和临床试验中进一步研究，以验证其在神经退行性疾病中的疗效。
