PDF(Pubmed)
Abstract：
UNASSIGNED: White matter loss is a well-documented phenomenon in Alzheimer\'s disease (AD) patients that has been recognized for decades. However, the underlying reasons for the failure of oligodendrocyte progenitor cells (OPCs) to repair myelin deficits in these patients remain elusive. A single nucleotide polymorphism (SNP) in Clusterin has been identified as a risk factor for late-onset Alzheimer\'s disease and linked to a decrease in white matter integrity in healthy adults, but its specific role in oligodendrocyte function and myelin maintenance in Alzheimer\'s disease pathology remains unclear.
UNASSIGNED: To investigate the impact of Clusterin on OPCs in the context of Alzheimer\'s disease, we employed a combination of immunofluorescence and transmission electron microscopy techniques, primary culture of OPCs, and an animal model of Alzheimer\'s disease.
UNASSIGNED: Our findings demonstrate that Clusterin, a risk factor for late-onset AD, is produced by OPCs and inhibits their differentiation into oligodendrocytes. Specifically, we observed upregulation of Clusterin in OPCs in the 5xFAD mouse model of AD. We also found that the phagocytosis of debris, including amyloid beta (Aβ), myelin, and apoptotic cells leads to the upregulation of Clusterin in OPCs. In vivo experiments confirmed that Aβ oligomers stimulate Clusterin upregulation and that OPCs are capable of phagocytosing Aβ. Furthermore, we discovered that Clusterin significantly inhibits OPC differentiation and hinders the production of myelin proteins. Finally, we demonstrate that Clusterin inhibits OPC differentiation by reducing the production of IL-9 by OPCs.
UNASSIGNED: Our data suggest that Clusterin may play a key role in the impaired myelin repair observed in AD and could serve as a promising therapeutic target for addressing AD-associated cognitive decline.
UNASSIGNED: To investigate the impact of Clusterin on OPCs in the context of Alzheimer\'s disease, we employed a combination of immunofluorescence and transmission electron microscopy techniques, primary culture of OPCs, and an animal model of Alzheimer\'s disease.
UNASSIGNED: Our findings demonstrate that Clusterin, a risk factor for late-onset AD, is produced by OPCs and inhibits their differentiation into oligodendrocytes. Specifically, we observed upregulation of Clusterin in OPCs in the 5xFAD mouse model of AD. We also found that the phagocytosis of debris, including amyloid beta (Aβ), myelin, and apoptotic cells leads to the upregulation of Clusterin in OPCs. In vivo experiments confirmed that Aβ oligomers stimulate Clusterin upregulation and that OPCs are capable of phagocytosing Aβ. Furthermore, we discovered that Clusterin significantly inhibits OPC differentiation and hinders the production of myelin proteins. Finally, we demonstrate that Clusterin inhibits OPC differentiation by reducing the production of IL-9 by OPCs.
UNASSIGNED: Our data suggest that Clusterin may play a key role in the impaired myelin repair observed in AD and could serve as a promising therapeutic target for addressing AD-associated cognitive decline.
摘要：
背景：白质损失是阿尔茨海默病（AD）患者中已被公认数十年的有据可查的现象。然而,这些患者少突胶质祖细胞(OPCs)修复髓鞘缺陷失败的根本原因仍然难以捉摸.Clusterin中的单核苷酸多态性（SNP）已被确定为迟发性阿尔茨海默病的危险因素，并与健康成人白质完整性降低有关。但其在阿尔茨海默病病理中的少突胶质细胞功能和髓鞘维持中的具体作用尚不清楚。
方法：为了研究Clusterin在阿尔茨海默病中对OPCs的影响，我们结合了免疫荧光和透射电子显微镜技术，OPCs的原代培养，和阿尔茨海默病的动物模型。
结果：我们的研究结果表明，Clusterin，迟发性AD的危险因素，由OPC产生并抑制它们分化为少突胶质细胞。具体来说,我们在5xFAD小鼠模型中观察到OPCs中Clusterin的上调。我们还发现碎片的吞噬作用，包括淀粉样蛋白β（Aβ），髓鞘,凋亡细胞导致OPCs中Clusterin的上调。体内实验证实Aβ寡聚体刺激Clusterin上调,并且OPC能够吞噬Aβ。此外，我们发现Clusterin显著抑制OPC分化并阻碍髓鞘蛋白的产生。最后,我们证明Clusterin通过减少OPC产生IL-9来抑制OPC分化。
结论：我们的数据表明，Clusterin可能在AD中观察到的髓鞘修复受损中起关键作用，并且可以作为解决AD相关认知衰退的有希望的治疗靶点。
方法：为了研究Clusterin在阿尔茨海默病中对OPCs的影响，我们结合了免疫荧光和透射电子显微镜技术，OPCs的原代培养，和阿尔茨海默病的动物模型。
结果：我们的研究结果表明，Clusterin，迟发性AD的危险因素，由OPC产生并抑制它们分化为少突胶质细胞。具体来说,我们在5xFAD小鼠模型中观察到OPCs中Clusterin的上调。我们还发现碎片的吞噬作用，包括淀粉样蛋白β（Aβ），髓鞘,凋亡细胞导致OPCs中Clusterin的上调。体内实验证实Aβ寡聚体刺激Clusterin上调,并且OPC能够吞噬Aβ。此外，我们发现Clusterin显著抑制OPC分化并阻碍髓鞘蛋白的产生。最后,我们证明Clusterin通过减少OPC产生IL-9来抑制OPC分化。
结论：我们的数据表明，Clusterin可能在AD中观察到的髓鞘修复受损中起关键作用，并且可以作为解决AD相关认知衰退的有希望的治疗靶点。
