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Abstract：
BACKGROUND: Alpha-lipoic acid (ALA) has a neuroprotective effect on neurodegenerative diseases. In the clinic, ALA can improve cognitive impairments in patients with Alzheimer\'s disease (AD) and other dementias. Animal studies have confirmed the anti-amyloidosis effect of ALA, but its underlying mechanism remains unclear. In particular, the role of ALA in amyloid-β precursor protein (APP) metabolism has not been fully elucidated.
OBJECTIVE: To investigate whether ALA can reduce the amyloidogenic effect of APP in a transgenic mouse model of AD, and to study the mechanism underlying this effect.
METHODS: ALA was infused into 2-month-old APP23/PS45 transgenic mice for 4 consecutive months and their cognitive function and AD-like pathology were then evaluated. An ALA drug concentration gradient was applied to 20E2 cells in vitro to evaluate its effect on the expression of APP proteolytic enzymes and metabolites. The mechanism by which ALA affects APP processing was studied using GI254023X, an inhibitor of A Disintegrin and Metalloproteinase 10 (ADAM10), as well as the mitochondrial toxic drug carbonyl cyanide m-chlorophenylhydrazone (CCCP).
RESULTS: Administration of ALA ameliorated amyloid plaque neuropathology in the brain tissue of APP23/PS45 mice and reduced learning and memory impairment. ALA also increased the expression of ADAM10 in 20E2 cells and the non-amyloidogenic processing of APP to produce the 83 amino acid C-terminal fragment (C83). In addition to activating autophagy, ALA also significantly promoted mitophagy. BNIP3L-knockdown reduced the mat/pro ratio of ADAM10. By using CCCP, ALA was found to regulate BNIP3L-mediated mitophagy, thereby promoting the α-cleavage of APP.
CONCLUSIONS: The enhanced α-secretase cleavage of APP by ADAM10 is the primary mechanism through which ALA ameliorates the cognitive deficits in APP23/PS45 transgenic mice. BNIP3L-mediated mitophagy contributes to the anti-amyloid properties of ALA by facilitating the maturation of ADAM10. This study provides novel experimental evidence for the treatment of AD with ALA.
OBJECTIVE: To investigate whether ALA can reduce the amyloidogenic effect of APP in a transgenic mouse model of AD, and to study the mechanism underlying this effect.
METHODS: ALA was infused into 2-month-old APP23/PS45 transgenic mice for 4 consecutive months and their cognitive function and AD-like pathology were then evaluated. An ALA drug concentration gradient was applied to 20E2 cells in vitro to evaluate its effect on the expression of APP proteolytic enzymes and metabolites. The mechanism by which ALA affects APP processing was studied using GI254023X, an inhibitor of A Disintegrin and Metalloproteinase 10 (ADAM10), as well as the mitochondrial toxic drug carbonyl cyanide m-chlorophenylhydrazone (CCCP).
RESULTS: Administration of ALA ameliorated amyloid plaque neuropathology in the brain tissue of APP23/PS45 mice and reduced learning and memory impairment. ALA also increased the expression of ADAM10 in 20E2 cells and the non-amyloidogenic processing of APP to produce the 83 amino acid C-terminal fragment (C83). In addition to activating autophagy, ALA also significantly promoted mitophagy. BNIP3L-knockdown reduced the mat/pro ratio of ADAM10. By using CCCP, ALA was found to regulate BNIP3L-mediated mitophagy, thereby promoting the α-cleavage of APP.
CONCLUSIONS: The enhanced α-secretase cleavage of APP by ADAM10 is the primary mechanism through which ALA ameliorates the cognitive deficits in APP23/PS45 transgenic mice. BNIP3L-mediated mitophagy contributes to the anti-amyloid properties of ALA by facilitating the maturation of ADAM10. This study provides novel experimental evidence for the treatment of AD with ALA.
摘要：
背景：α-硫辛酸（ALA）对神经退行性疾病具有神经保护作用。在诊所里,ALA可以改善阿尔茨海默病（AD）和其他痴呆患者的认知功能损害。动物研究证实了ALA的抗淀粉样变性作用，但其潜在机制仍不清楚。特别是,ALA在淀粉样β前体蛋白（APP）代谢中的作用尚未完全阐明。
目的：研究ALA在AD转基因小鼠模型中是否能降低APP的淀粉样生成作用，并研究这种效应的潜在机制。
方法：对2月龄的APP23/PS45转基因小鼠连续4个月输入ALA，然后评估其认知功能和AD样病理。将ALA药物浓度梯度应用于体外20E2细胞，以评估其对APP蛋白水解酶和代谢产物表达的影响。使用GI254023X研究了ALA影响APP加工的机制，解整合素和金属蛋白酶10（ADAM10）的抑制剂，以及线粒体毒性药物羰基氰化物间氯苯腙（CCCP）。
结果:施用ALA改善了APP23/PS45小鼠脑组织中的淀粉样蛋白斑神经病理学,并减少了学习和记忆障碍。ALA还增加了ADAM10在20E2细胞中的表达和APP的非淀粉样蛋白生成加工以产生83个氨基酸的C末端片段(C83)。除了激活自噬，ALA还显著促进线粒体自噬。BNIP3L敲低降低了ADAM10的mat/pro比。通过使用CCCP，发现ALA调节BNIP3L介导的线粒体自噬，从而促进APP的α-裂解。
结论：ADAM10增强APP的α-分泌酶裂解是ALA改善APP23/PS45转基因小鼠认知缺陷的主要机制。BNIP3L介导的线粒体自噬通过促进ADAM10的成熟而有助于ALA的抗淀粉样蛋白特性。本研究为ALA治疗AD提供了新的实验证据。
目的：研究ALA在AD转基因小鼠模型中是否能降低APP的淀粉样生成作用，并研究这种效应的潜在机制。
方法：对2月龄的APP23/PS45转基因小鼠连续4个月输入ALA，然后评估其认知功能和AD样病理。将ALA药物浓度梯度应用于体外20E2细胞，以评估其对APP蛋白水解酶和代谢产物表达的影响。使用GI254023X研究了ALA影响APP加工的机制，解整合素和金属蛋白酶10（ADAM10）的抑制剂，以及线粒体毒性药物羰基氰化物间氯苯腙（CCCP）。
结果:施用ALA改善了APP23/PS45小鼠脑组织中的淀粉样蛋白斑神经病理学,并减少了学习和记忆障碍。ALA还增加了ADAM10在20E2细胞中的表达和APP的非淀粉样蛋白生成加工以产生83个氨基酸的C末端片段(C83)。除了激活自噬，ALA还显著促进线粒体自噬。BNIP3L敲低降低了ADAM10的mat/pro比。通过使用CCCP，发现ALA调节BNIP3L介导的线粒体自噬，从而促进APP的α-裂解。
结论：ADAM10增强APP的α-分泌酶裂解是ALA改善APP23/PS45转基因小鼠认知缺陷的主要机制。BNIP3L介导的线粒体自噬通过促进ADAM10的成熟而有助于ALA的抗淀粉样蛋白特性。本研究为ALA治疗AD提供了新的实验证据。
