Abstract：
BACKGROUND: Alzheimer\'s disease (AD), the most common neurodegenerative disorder, affects a broad spectrum of aging populations. AD is characterized by pathological amyloid-β (Aβ) plaques and neurofibrillary tangles, leading to neural degeneration and cognitive decline. The lack of effective treatments for AD highlights the urgent need for novel therapeutic agents, particularly in the early stages. Dimethylsulfoniopropionate (DMSP) is a natural marine compound with antioxidant and neuroprotective properties. However, studies on the efficacy of DMSP in the treatment of AD and its associated mechanisms are limited.
OBJECTIVE: This study aimed to explore the therapeutic effects and mechanisms of action of DMSP as an AD treatment using a preclinical 3 × Tg-AD mouse model.
METHODS: The research involved administering DMSP (7 μg/mL and 11 μg/mL in drinking water) to four-month-old 3 × Tg-AD mice consecutively for three months. The Y-maze test, novel object recognition test, and Morris water maze test were used to assess memory and learning ability. The relative expression levels and distribution of proteins relevant to Aβ and tau pathology, synapses, and glial cells were analyzed using western blotting and immunofluorescence assays. Additionally, proteomic and bioinformatics approaches were used to explore the potential targets of DMSP treatment.
RESULTS: DMSP-treated AD mice showed significantly enhanced cognitive function, suggesting that DMSP mitigates memory and learning impairments in AD. Moreover, DMSP diminished the abnormal accumulation of Aβ and phosphorylated tau in both the cortex and hippocampus, which are crucial hallmarks of AD pathology. In addition to its neuroprotective properties, DMSP restored synaptic density and the expression of synaptic and neuronal proteins, which are essential for proper brain function. DMSP displayed anti-inflammatory properties, as evidenced by its ability to suppress inflammatory astrocytes and maintain microglial homeostasis. Notably, DMSP facilitated the maturation of oligodendrocytes (OLs) from oligodendrocyte progenitor cells (OPCs), a critical process in the development of the brain myelination architecture. Proteomic analysis revealed that DMSP positively influenced biological processes crucial for oligodendrocyte development, myelination, and axonal ensheathment, which are often compromised in patients with AD. Protein validation and brain tissue staining supported the role of DMSP in preserving myelin enrichment and sheath integrity. These therapeutic effects were largely attributed to the enhanced expression of myelin-associated glycoprotein (Mag) and tetraspanin Cd9.
CONCLUSIONS: Overall, our findings highlight DMSP as a promising novel therapeutic candidate for AD, offering multifaceted benefits in cognitive and memory enhancement, reduction of Aβ and tau pathology, neuronal synapse protection, anti-inflammatory effects, and myelin sheath restoration as an innovative target compared to other studies. In addition to being a potentially effective treatment for AD, DMSP may also have the potential to address other neurodegenerative diseases that are closely associated with myelin impairment.
OBJECTIVE: This study aimed to explore the therapeutic effects and mechanisms of action of DMSP as an AD treatment using a preclinical 3 × Tg-AD mouse model.
METHODS: The research involved administering DMSP (7 μg/mL and 11 μg/mL in drinking water) to four-month-old 3 × Tg-AD mice consecutively for three months. The Y-maze test, novel object recognition test, and Morris water maze test were used to assess memory and learning ability. The relative expression levels and distribution of proteins relevant to Aβ and tau pathology, synapses, and glial cells were analyzed using western blotting and immunofluorescence assays. Additionally, proteomic and bioinformatics approaches were used to explore the potential targets of DMSP treatment.
RESULTS: DMSP-treated AD mice showed significantly enhanced cognitive function, suggesting that DMSP mitigates memory and learning impairments in AD. Moreover, DMSP diminished the abnormal accumulation of Aβ and phosphorylated tau in both the cortex and hippocampus, which are crucial hallmarks of AD pathology. In addition to its neuroprotective properties, DMSP restored synaptic density and the expression of synaptic and neuronal proteins, which are essential for proper brain function. DMSP displayed anti-inflammatory properties, as evidenced by its ability to suppress inflammatory astrocytes and maintain microglial homeostasis. Notably, DMSP facilitated the maturation of oligodendrocytes (OLs) from oligodendrocyte progenitor cells (OPCs), a critical process in the development of the brain myelination architecture. Proteomic analysis revealed that DMSP positively influenced biological processes crucial for oligodendrocyte development, myelination, and axonal ensheathment, which are often compromised in patients with AD. Protein validation and brain tissue staining supported the role of DMSP in preserving myelin enrichment and sheath integrity. These therapeutic effects were largely attributed to the enhanced expression of myelin-associated glycoprotein (Mag) and tetraspanin Cd9.
CONCLUSIONS: Overall, our findings highlight DMSP as a promising novel therapeutic candidate for AD, offering multifaceted benefits in cognitive and memory enhancement, reduction of Aβ and tau pathology, neuronal synapse protection, anti-inflammatory effects, and myelin sheath restoration as an innovative target compared to other studies. In addition to being a potentially effective treatment for AD, DMSP may also have the potential to address other neurodegenerative diseases that are closely associated with myelin impairment.
摘要：
背景：阿尔茨海默病（AD），最常见的神经退行性疾病，影响了广泛的老龄化人口。AD的特征是病理性淀粉样β（Aβ）斑块和神经原纤维缠结，导致神经退化和认知能力下降。缺乏有效的AD治疗方法凸显了对新型治疗剂的迫切需求。特别是在早期阶段。二甲基磺丙酸酯（DMSP）是一种具有抗氧化和神经保护特性的天然海洋化合物。然而,关于DMSP治疗AD的疗效及其相关机制的研究有限。
目的：本研究旨在使用临床前3×Tg-AD小鼠模型探索DMSP作为AD治疗的治疗效果和作用机制。
方法：研究涉及对四个月大的3×Tg-AD小鼠连续三个月给予DMSP（饮用水中7μg/mL和11μg/mL）。Y迷宫测试,新颖的物体识别测试，采用Morris水迷宫测验评价记忆和学习能力。Aβ和tau病理相关蛋白的相对表达水平和分布,突触，和神经胶质细胞使用蛋白质印迹和免疫荧光分析。此外,蛋白质组学和生物信息学方法用于探索DMSP治疗的潜在靶标。
结果：DMSP治疗的AD小鼠表现出显著增强的认知功能，提示DMSP减轻AD患者的记忆和学习障碍。此外，DMSP减少了皮质和海马中Aβ和磷酸化tau的异常积累，这是AD病理学的关键标志。除了它的神经保护特性，DMSP恢复突触密度以及突触和神经元蛋白的表达，这对正常的大脑功能至关重要。DMSP显示抗炎特性，其抑制炎性星形胶质细胞和维持小胶质细胞稳态的能力证明了这一点。值得注意的是,DMSP促进少突胶质细胞祖细胞（OPCs）的成熟，大脑髓鞘形成结构发展的关键过程。蛋白质组学分析显示，DMSP积极影响对少突胶质细胞发育至关重要的生物过程，髓鞘形成,和轴突鞘，在AD患者中经常受损。蛋白质验证和脑组织染色支持DMSP在保持髓鞘富集和鞘完整性中的作用。这些治疗效果很大程度上归因于髓鞘相关糖蛋白(Mag)和四跨膜蛋白Cd9的表达增强。
结论：总体而言，我们的发现强调DMSP是一种有前途的新型AD治疗候选药物，在认知和记忆增强方面提供多方面的好处，减少Aβ和tau病理，神经元突触保护，抗炎作用，与其他研究相比，髓鞘修复是一个创新的目标。除了是一个潜在的有效治疗AD，DMSP还可能具有解决与髓磷脂损伤密切相关的其他神经退行性疾病的潜力。
目的：本研究旨在使用临床前3×Tg-AD小鼠模型探索DMSP作为AD治疗的治疗效果和作用机制。
方法：研究涉及对四个月大的3×Tg-AD小鼠连续三个月给予DMSP（饮用水中7μg/mL和11μg/mL）。Y迷宫测试,新颖的物体识别测试，采用Morris水迷宫测验评价记忆和学习能力。Aβ和tau病理相关蛋白的相对表达水平和分布,突触，和神经胶质细胞使用蛋白质印迹和免疫荧光分析。此外,蛋白质组学和生物信息学方法用于探索DMSP治疗的潜在靶标。
结果：DMSP治疗的AD小鼠表现出显著增强的认知功能，提示DMSP减轻AD患者的记忆和学习障碍。此外，DMSP减少了皮质和海马中Aβ和磷酸化tau的异常积累，这是AD病理学的关键标志。除了它的神经保护特性，DMSP恢复突触密度以及突触和神经元蛋白的表达，这对正常的大脑功能至关重要。DMSP显示抗炎特性，其抑制炎性星形胶质细胞和维持小胶质细胞稳态的能力证明了这一点。值得注意的是,DMSP促进少突胶质细胞祖细胞（OPCs）的成熟，大脑髓鞘形成结构发展的关键过程。蛋白质组学分析显示，DMSP积极影响对少突胶质细胞发育至关重要的生物过程，髓鞘形成,和轴突鞘，在AD患者中经常受损。蛋白质验证和脑组织染色支持DMSP在保持髓鞘富集和鞘完整性中的作用。这些治疗效果很大程度上归因于髓鞘相关糖蛋白(Mag)和四跨膜蛋白Cd9的表达增强。
结论：总体而言，我们的发现强调DMSP是一种有前途的新型AD治疗候选药物，在认知和记忆增强方面提供多方面的好处，减少Aβ和tau病理，神经元突触保护，抗炎作用，与其他研究相比，髓鞘修复是一个创新的目标。除了是一个潜在的有效治疗AD，DMSP还可能具有解决与髓磷脂损伤密切相关的其他神经退行性疾病的潜力。
