Department of Translational Neuroscience, Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG Utrecht, The Netherlands; Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, 1098 XH Amsterdam, The Netherlands.
Department of Translational Neuroscience, Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG Utrecht, The Netherlands.
Brain Behav Immun. 2022 Feb;100:219-230. doi: 10.1016/j.bbi.2021.12.001. Epub 2021 Dec 9.
Dysregulation of microglial function contributes to Alzheimer's disease (AD) pathogenesis. Several genetic and transcriptome studies have revealed microglia specific genetic risk factors, and changes in microglia expression profiles in AD pathogenesis, viz. the human-Alzheimer's microglia/myeloid (HAM) profile in AD patients and the disease-associated microglia profile (DAM) in AD mouse models. The transcriptional changes involve genes in immune and inflammatory pathways, and in pathways associated with Aβ clearance. Aβ oligomers have been suggested to be the initial trigger of microglia activation in AD. To study the direct response to Aβ oligomers exposure, we assessed changes in gene expression in an in vitro model for microglia, the human monocyte-derived microglial-like (MDMi) cells. We confirmed the initiation of an inflammatory profile following LPS stimulation, based on increased expression of IL1B, IL6, and TNFα. In contrast, the Aβ oligomers did not induce an inflammatory profile or a classical HAM profile. Interestingly, we observed a specific increase in the expression of metallothioneins in the Aβ oligomer treated MDMi cells. Metallothioneins are involved in metal ion regulation, protection against reactive oxygen species, and have anti-inflammatory properties. In conclusion, our data suggests that exposure to Aβ oligomers may initially trigger a protective response in vitro.
小胶质细胞功能失调导致阿尔茨海默病（AD）的发病机制。几项遗传和转录组研究揭示了小胶质细胞特异性遗传风险因素，以及 AD 发病过程中小胶质细胞表达谱的变化，即 AD 患者的人类阿尔茨海默病小胶质细胞/髓样细胞（HAM）谱和 AD 小鼠模型中的疾病相关小胶质细胞谱。转录变化涉及免疫和炎症途径以及与 Aβ清除相关的途径中的基因。Aβ寡聚体被认为是 AD 中小胶质细胞激活的初始触发因素。为了研究对 Aβ寡聚体暴露的直接反应，我们评估了体外小胶质细胞模型中人单核细胞衍生的小胶质样（MDMi）细胞中基因表达的变化。我们证实了 LPS 刺激后炎症谱的启动，这是基于 IL1B、IL6 和 TNFα 的表达增加。相比之下，Aβ 寡聚体不会诱导炎症谱或典型的 HAM 谱。有趣的是，我们观察到在 Aβ 寡聚体处理的 MDMi 细胞中金属硫蛋白的表达特异性增加。金属硫蛋白参与金属离子调节、抵抗活性氧和具有抗炎特性。总之，我们的数据表明，Aβ 寡聚体的暴露可能会在体外引发最初的保护反应。
