König Jennifer, Blusch Alina, Fatoba Oluwaseun, Gold Ralf, Saft Carsten, Ellrichmann-Wilms Gisa
Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany.
Department of Physiology and Pathophysiology, Center of Biomedical Education and Research (ZBAF), Faculty of Health, School of Medicine, Witten/Herdecke University, 58453 Witten, Germany.
Int J Mol Sci. 2025 Apr 2;26(7):3318. doi: 10.3390/ijms26073318.
Huntington's disease is a progressive, untreatable neurodegenerative disorder caused by a mutation in the Huntingtin gene. Next to neurodegeneration, altered immune activation is involved in disease progression. Since central nervous system inflammation and dysfunction of immune cells are recognized as driving characteristics, immunomodulation might represent an additional therapeutic strategy. Short-chain fatty acids were known to have immunomodulatory effects in neuroinflammatory diseases, such as multiple sclerosis. In this study, R6/2 mice were treated daily with 150 mM propionate. Survival range, body weight, and motor abilities were monitored. In striatal and cortical samples, neuronal survival was analyzed by immunofluorescence staining of NeuN-positive cells and expression levels of BDNF mRNA by real-time polymerase chain reaction. As inflammatory marker TNFα mRNA and IL-6 mRNA were quantified by rtPCR, iNOS-expressing cells were counted in immunologically stained brain slides. Microglial activation was evaluated by immunofluorescent staining of IBA1-positive cells and total IBA1 protein by Western Blot, in addition, SPI1 mRNA expression was quantified by rtPCR. Except for clasping behavior, propionate treatment did neither improve the clinical course nor mediated neuronal protection in R6/2 mice. Yet there was a mild anti-inflammatory effect in the CNS, with (i) reduction in SPI1-mRNA levels, (ii) reduced iNOS positive cells in the motor cortex, and (iii) normalized TNFα-mRNA in the motor cortex of propionate-treated R6/2 mice. Thus, Short-chain fatty acids, as an environmental factor in the diet, may slightly alleviate symptoms by down-regulating inflammatory factors in the central nervous system. However, they cannot prevent clinical disease progression or neuronal loss.
亨廷顿舞蹈症是一种由亨廷顿基因发生突变引起的进行性、无法治愈的神经退行性疾病。除神经退行性变外，免疫激活改变也参与疾病进展。由于中枢神经系统炎症和免疫细胞功能障碍被认为是主要特征，免疫调节可能是一种额外的治疗策略。已知短链脂肪酸在神经炎症性疾病（如多发性硬化症）中具有免疫调节作用。在本研究中，每天用150 mM丙酸盐处理R6/2小鼠。监测其存活范围、体重和运动能力。在纹状体和皮质样本中，通过NeuN阳性细胞的免疫荧光染色分析神经元存活情况，并通过实时聚合酶链反应分析脑源性神经营养因子（BDNF）mRNA的表达水平。通过rtPCR定量分析炎症标志物肿瘤坏死因子α（TNFα）mRNA和白细胞介素-6（IL-6）mRNA，在免疫染色的脑切片中计数诱导型一氧化氮合酶（iNOS）表达细胞。通过IBA1阳性细胞的免疫荧光染色和蛋白质免疫印迹法检测总IBA1蛋白来评估小胶质细胞激活，此外，通过rtPCR定量分析SPI1 mRNA表达。除了抓握行为外，丙酸盐处理既没有改善R6/2小鼠的临床病程，也没有介导神经元保护作用。然而，在中枢神经系统中存在轻微的抗炎作用，表现为：（i）SPI1-mRNA水平降低；（ii）运动皮质中iNOS阳性细胞减少；（iii）丙酸盐处理的R6/2小鼠运动皮质中TNFα-mRNA水平恢复正常。因此，短链脂肪酸作为饮食中的一个环境因素，可能通过下调中枢神经系统中的炎症因子来轻微缓解症状。然而，它们不能阻止临床疾病进展或神经元丢失。
