Vitamin B12 may prevent Aβ oligomer‐induced neurotoxicity in Alzheimer's disease
Vitamin B12 may prevent Aβ oligomer‐induced neurotoxicity in Alzheimer's disease
复制标题
维生素 B12 可预防 Aβ 寡聚物引起的阿尔茨海默病神经毒性
DOI：
10.1002/alz.045043
复制
发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Atsushi Michael Kimura
中科院分区：
文献类型：
--
作者：
Nakano Takahiro;Uchiyama Kazuhiko;Ushiroda Chihiro;Kashiwagi Saori;Toyokawa Yuki;Mizushima Katsura;Inoue Ken;Dohi Osamu;Okayama Tetsuya;Yoshida Naohisa;Katada Kazuhiro;Kamada Kazuhiro;Handa Osamu;Ishikawa Takeshi;Takagi Tomohisa;Konishi Hideyuki;Naito Yuj;Atsushi Michael Kimura
β-淀粉样多肽(A-β)过度蓄积是阿尔茨海默病(AD)神经元死亡的主要机制之一。我们之前已经证明了原纤维，一种积累的Aβ寡聚体，被认为起到了重要作用。维生素B12是脑发育所必需的一种重要的微量营养素，因其能改善轻度认知障碍患者的认知状态而备受关注，但其对Aβ寡聚体诱导的神经毒性的保护作用尚不清楚。最近，我们发现AD患者的血VB12水平与一些主要的认知功能显著相关。本研究旨在阐明维生素B_(12)对A-β寡聚体所致神经毒性的保护作用机制。方法采用体积排阻层析法洗脱β(1-42)寡聚体。用5-μ-M-A-β寡聚体诱导人神经母细胞瘤细胞(SH-SY5Y)神经元损伤。SH-SY5Y细胞用VB12(50μM)与A-β寡聚体联合作用30min~3h。用四甲基偶氮唑盐(3‐[4，5‐dimethylthiazole‐2‐yl]‐2，5‐diphenyltetrazolium)比色法和线粒体膜电位分析法检测Aβ寡聚体对细胞的毒性作用。结果β寡聚体(1、2.5、5、10μM)暴露使细胞存活率下降，呈剂量依赖关系。然而，VB12处理显著恢复了Aβ寡聚体处理所降低的细胞存活率。Aβ寡聚体可显著降低线粒体膜电位，VB12可显著抑制线粒体膜电位的下降，提示线粒体参与了Aβ寡聚体所致的神经元损伤。β寡聚体可增加细胞内ROS、线粒体ROS和质膜磷脂过氧化产物，VB12可减轻Aβ寡聚体引起的氧化应激增加。结论VB12可抑制Aβ寡聚体引起的氧化应激所致的线粒体崩溃。VB12可作为预防神经元损伤的治疗剂和治疗AD患者认知障碍的候选药物。
BackgroundExcessive accumulation of β‐amyloid peptide (Aβ) is one of the major mechanisms that cause neuronal death in Alzheimer's disease (AD). We’ve previously shown protofibrils, one of the accumulated Aβ oligomers, are implicated to play a major role. Vitamin B12 (VB12) is an important micronutrient required for brain development and has received attention because of its ability to improve cognitive status in Mild Cognitive Impairment(MCI).However, the protective effects of VB12 against Aβ oligomer‐induced neurotoxicity remain unclear. Recently, we found blood VB12 levels in AD patients are significantly associated with some of the major cognitive functions. Besides, it was associated with left hippocampal blood flow.The purpose of this study was to clarify the mechanism of the protective effect of VB12 against the Aβ oligomer‐induced neurotoxicity.MethodAβ(1‐42) oligomer was eluted using size exclusion chromatography. Neuronal damage was induced in human neuroblastoma cells (SH‐SY5Y) using 5 μM Aβ oligomer. SH‐SY5Y cells were treated with VB12 (50 μM) for 30 min ‐3 hours in combination with Aβ oligomer. Cytotoxicity of Aβ oligomer‐exposed cells was assessed by the 3‐[4,5‐dimethylthiazole‐2‐yl]‐2,5‐diphenyltetrazolium bromide (MTT) and mitochondrial membrane potential (MMP) analyses. Oxidative stress was evaluated by measuring products of reactive oxygen species (ROS), mitochondrial ROS and phospholipid peroxides of plasma cell membranes.ResultAβ oligomers (1, 2.5, 5 and 10 μM) exposure decreased cell viability in a dose‐dependent manner. However, treatment with VB12 significantly recovered the cell viability that was reduced by treatment with Aβ oligomer. MMP significantly decreased with Aβ oligomer and the decrease was significantly suppressed with treatment with VB12, indicating that mitochondria were involved in the neuronal damage induced by Aβ oligomer exposure. Aβ oligomer increased intracellular ROS, mitochondrial ROS and phospholipid peroxides of the plasma membrane, and the increase in Aβ oligomer‐induced oxidative stress was reduced by VB12 treatment.ConclusionThese results suggested that the collapse of mitochondria induced by oxidative stress associated with Aβ oligomer exposure was suppressed by treatment with VB12. VB12 may be provided as a therapeutic agent for the prevention of neuronal damage and as a candidate for the treatment of cognitive impairments in AD patients.