The Second Affiliated Hospital of Jiaxing University, Jiaxing 314000, China.
The Second Affiliated Hospital of Jiaxing University, Jiaxing 314000, China.
Prog Neuropsychopharmacol Biol Psychiatry. 2020 Jun 8;100:109884. doi: 10.1016/j.pnpbp.2020.109884. Epub 2020 Feb 4.
Alzheimer's disease (AD) is a central degenerative disease characterized by cognitive impairment. Polymerization of β-amyloid has been reported to cause the entanglement of nerve cells, leading to the progressive loss of nerve cells. Accumulative studies have confirmed the important roles of neuroinflammation in the development of AD. In this study, the gut microbiota from AD patients were transplanted into APP/PS1 double transgenic mice. As a result, the expression of NLRP3 was increased in the intestinal tract of mice, and the expression levels of inflammatory factors in peripheral blood were also increased. Consistently, the cognitive impairment was more severe in mice receiving gut microbiota from AD patients than those did not, with activation of microglia in the central hippocampus of mice, and increased expression of neuroinflammatory factors. In APP/PS1 mice transplanted with gut microbiota from AD patients, transplantation of healthy human gut microbiota or oral administration of minocycline was further used to improve the composition of gut microbiota. Consequently, the intestinal expression of NLRP3 was down-regulated, the cognitive ability of mice was improved, the activation of microglia in central hippocampus was suppressed and the expression of neuroinflammatory factors was also down-regulated. After transplantation of gut microbiota from AD patients in C57BL/6 mice, the intestinal expression of NLRP3 was up-regulated. Although the cognitive ability of mice was not significantly changed, the microglia in the hippocampus of mice were still activated and the expression of inflammatory factors was up-regulated. In this study, we found that gut microbiota in AD patients could induce the activation of NLRP3 inflammasome in the intestinal tract of mice, subsequently causing the release of inflammatory factors. The absorption and circulation of inflammatory factors through the intestinal tract could further aggravate the inflammation in the nervous tissues and the activation of microglia. Therefore, improving the composition of gut microbiota in AD patients can further attenuate neuroinflammation, which is considered as a novel idea for AD treatment.
阿尔茨海默病（AD）是一种以认知障碍为特征的中枢退行性疾病。有报道称β-淀粉样蛋白的聚合会导致神经细胞缠结，从而导致神经细胞逐渐丧失。累积的研究证实了神经炎症在 AD 发展中的重要作用。在这项研究中，将 AD 患者的肠道微生物群移植到 APP/PS1 双转基因小鼠中。结果，小鼠肠道中 NLRP3 的表达增加，外周血中炎症因子的表达水平也升高。一致地，接受 AD 患者肠道微生物群移植的小鼠认知障碍比未接受的更严重，小鼠中枢海马区的小胶质细胞被激活，神经炎症因子的表达增加。在接受 AD 患者肠道微生物群移植的 APP/PS1 小鼠中，进一步移植健康人肠道微生物群或口服米诺环素以改善肠道微生物群的组成。结果，肠道中 NLRP3 的表达下调，小鼠的认知能力提高，中枢海马区小胶质细胞的激活受到抑制，神经炎症因子的表达也下调。在将 AD 患者的肠道微生物群移植到 C57BL/6 小鼠后，肠道中 NLRP3 的表达上调。虽然小鼠的认知能力没有明显变化，但小鼠海马区的小胶质细胞仍被激活，炎症因子的表达上调。在这项研究中，我们发现 AD 患者的肠道微生物群可以诱导小鼠肠道中 NLRP3 炎性小体的激活，随后导致炎症因子的释放。炎症因子通过肠道的吸收和循环可以进一步加重神经组织中的炎症和小胶质细胞的激活。因此，改善 AD 患者肠道微生物群的组成可以进一步减轻神经炎症，这被认为是 AD 治疗的新想法。
