Cognition & Behavioral Neurology Section, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences & Technology (SCTIMST), Thiruvananthapuram, Kerala, India.
Department of Biochemistry, Sree Chitra Tirunal Institute for Medical Sciences & Technology (SCTIMST), Thiruvananthapuram, Kerala, 695011, India.
Cell Mol Neurobiol. 2019 Apr;39(3):355-369. doi: 10.1007/s10571-019-00651-1. Epub 2019 Jan 29.
Peripheral blood-derived macrophages isolated from Alzheimer's disease (AD) patients have earlier been reported to demonstrate ineffective phagocytosis of amyloid-beta compared to the age-matched control subjects. However, the mechanisms causing unsuccessful phagocytosis remain unclear. Oxidative stress and the presence of ApoEε4 allele has been reported to play a major role in the pathogenesis of AD, but the contribution of oxidative stress and ApoEε4 in macrophage dysfunction leading to ineffective Aβ phagocytosis needs to be analyzed. Aβ phagocytosis assay has been performed using FITC-labeled Aβ and analyzed using flow cytometry and confocal imaging in patient samples and in THP-1 cells. Oxidative stress in patient-derived macrophages was analyzed by assessing the DNA damage using comet assay. ApoE polymorphism was analyzed using sequence-specific PCR and Hixson & Vernier Restriction isotyping protocol. In this study, we have analyzed the patterns of phagocytic inefficiency of macrophages in Indian population with a gradual decline in the phagocytic potential from mild cognitive impairment (MCI) to AD patients. Further, we have shown that the presence of ApoEε4 allele might also have a possible effect on the phagocytosis efficiency of the macrophages. Here, we demonstrate for the first time that oxidative stress could affect the amyloid-beta phagocytic potential of macrophages and hence by alleviating oxidative stress using curcumin, an anti-oxidant could enhance the amyloid-beta phagocytic efficacy of macrophages of patients with AD and MCI, although the responsiveness to curcumin might depends on the presence or absence of APOEε4 allele. Oxidative stress contributes significantly to decreased phagocytosis of Aβ by macrophages. Moreover, the phagocytic inefficiency of macrophages was correlated to the presence of ApoEε4 allele. This study also found that the Aβ-phagocytic potential of macrophage gets significantly enhanced in curcumin-treated patient-derived macrophages.
从阿尔茨海默病（AD）患者外周血中分离出的巨噬细胞，与年龄匹配的对照组相比，先前已被报道表现出对淀粉样β（Aβ）的吞噬作用无效。然而，导致吞噬作用失败的机制仍不清楚。氧化应激和载脂蛋白 Eε4 等位基因的存在已被报道在 AD 的发病机制中起主要作用，但氧化应激和 ApoEε4 在导致巨噬细胞功能障碍和 Aβ吞噬作用无效中的作用需要进行分析。使用 FITC 标记的 Aβ 进行 Aβ吞噬作用测定，并使用流式细胞术和共聚焦成像在患者样本和 THP-1 细胞中进行分析。使用彗星试验评估 DNA 损伤来分析患者来源的巨噬细胞中的氧化应激。使用序列特异性 PCR 和 Hixson & Vernier 限制酶切分型方案分析 ApoE 多态性。在这项研究中，我们分析了印度人群中巨噬细胞吞噬作用效率低下的模式，从轻度认知障碍（MCI）到 AD 患者，吞噬作用潜力逐渐下降。此外，我们还表明，ApoEε4 等位基因的存在也可能对巨噬细胞的吞噬作用效率产生影响。在这里，我们首次证明氧化应激可能会影响巨噬细胞对 Aβ的吞噬能力，因此通过使用姜黄素缓解氧化应激，一种抗氧化剂可以增强 AD 和 MCI 患者巨噬细胞对 Aβ的吞噬作用效率，尽管对姜黄素的反应可能取决于 APOEε4 等位基因的存在与否。氧化应激对巨噬细胞对 Aβ的吞噬作用有显著影响。此外，巨噬细胞的吞噬作用效率与 ApoEε4 等位基因的存在相关。这项研究还发现，姜黄素处理后的患者来源巨噬细胞的 Aβ吞噬能力显著增强。
