Alzheimer’s disease (AD) is the most common neurodegenerative disease ultimately manifesting as clinical dementia. Despite considerable effort and ample experimental data, the role of neuroinflammation related to systemic inflammation is still unsettled. While the implication of microglia is well recognized, the exact contribution of peripheral monocytes/macrophages is still largely unknown, especially concerning their role in the various stages of AD. AD develops over decades and its clinical manifestation is preceded by subjective memory complaints (SMC) and mild cognitive impairment (MCI); thus, the question arises how the peripheral innate immune response changes with the progression of the disease. Therefore, to further investigate the roles of monocytes/macrophages in the progression of AD we assessed their phenotypes and functions in patients at SMC, MCI and AD stages and compared them with cognitively healthy controls. We also conceptualised an idealised mathematical model to explain the functionality of monocytes/macrophages along the progression of the disease. We show that there are distinct phenotypic and functional changes in monocyte and macrophage populations as the disease progresses. Higher free radical production upon stimulation could already be observed for the monocytes of SMC patients. The most striking results show that activation of peripheral monocytes (hyperactivation) is the strongest in the MCI group, at the prodromal stage of the disease. Monocytes exhibit significantly increased chemotaxis, free radical production, and cytokine production in response to TLR2 and TLR4 stimulation. Our data suggest that the peripheral innate immune system is activated during the progression from SMC through MCI to AD, with the highest levels of activation being in MCI subjects and the lowest in AD patients. Some of these parameters may be used as biomarkers, but more holistic immune studies are needed to find the best period of the disease for clinical intervention.

中文翻译：

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MCI患者单核细胞和巨噬细胞的过度活化有助于阿尔茨海默病的进展

阿尔茨海默病 (AD) 是最常见的神经退行性疾病，最终表现为临床痴呆。尽管付出了相当大的努力和充足的实验数据，但与全身炎症相关的神经炎症的作用仍未确定。虽然小胶质细胞的影响已得到广泛认可，但外周单核细胞/巨噬细胞的确切贡献在很大程度上仍是未知的，尤其是关于它们在 AD 各个阶段中的作用。AD 发展数十年，其临床表现先于主观记忆障碍 (SMC) 和轻度认知障碍 (MCI)；因此，问题出现了，外周先天免疫反应如何随着疾病的进展而变化。所以，为了进一步研究单核细胞/巨噬细胞在 AD 进展中的作用，我们评估了它们在 SMC、MCI 和 AD 阶段患者中的表型和功能，并将它们与认知健康的对照组进行了比较。我们还概念化了一个理想化的数学模型来解释单核细胞/巨噬细胞在疾病进展过程中的功能。我们表明，随着疾病的进展，单核细胞和巨噬细胞群存在明显的表型和功能变化。对于 SMC 患者的单核细胞，已经可以观察到刺激后产生更高的自由基。最引人注目的结果表明，在疾病的前驱阶段，外周单核细胞的激活（过度激活）在 MCI 组中最强。单核细胞表现出显着增加的趋化性、自由基产生、和响应 TLR2 和 TLR4 刺激的细胞因子产生。我们的数据表明，在从 SMC 到 MCI 到 AD 的进展过程中，外周先天免疫系统被激活，其中 MCI 受试者的激活水平最高，AD 患者的激活水平最低。其中一些参数可用作生物标志物，但需要更全面的免疫研究来找到疾病的最佳临床干预期。