單核球在阿茲海默症中的雙面刃：從臨床觀察到動物研究

The Double-Edged Sword of Monocytes in Alzheimer’s Disease: From Clinical Observations to Preclinical Models

阿茲海默症（Alzheimer’s disease, AD）是全球最常見影響老年人的神經退化性疾病之一。這是一種進行性疾病，其特徵是細胞外澱粉樣β斑塊的積聚和細胞內神經纖維纏結內過度磷酸化的tau蛋白的堆積，這兩者都是阿茲海默症病理的標誌性特徵。對死後病人海馬迴腦組織的免疫染色結果進行分析顯示，在疾病晚期，單核球會浸潤到腦實質之中。此外，過去研究也顯示，阿茲海默症所致之疾病早期的輕度認知障礙，患者之循環中單核球和巨噬細胞可見過度活躍現象，並且與病情進展加速有關。雖然大腦中的駐地巨噬細胞-微膠質細胞（microglia）已被證實是中樞神經系統免疫反應的重要角色和阿茲海默症發病機制的關鍵參與者，但浸潤性骨髓系細胞，尤其是單核球，在疾病中的功能仍有爭議。在這篇綜論中，我們綜合了分析阿茲海默症患者周邊血液、腦脊髓液和死後腦組織中的單核球之臨床研究證據，以及澱粉樣β斑塊和tau蛋白的推積病理的臨床前小鼠模型的發現，以闡明單核球在阿茲海默症進展和神經病理學中的異質性和雙重有益與有害作用。

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder affecting older adults worldwide. It is a progressive condition characterized by the accumulation of extracellular amyloid-βplaques and intracellular aggregates of hyperphosphorylated tau within neurofibrillary tangles, both of which are hallmark features of AD pathology. Immunohistochemical analyses of post-mortem human hippocampal tissue have revealed the infiltration of monocyte derivatives into the brain parenchyma during advanced stages of the disease. Furthermore, hyperactivation of circulating monocytes and macrophages has been reported in patients with mild cognitive impairment, a prodromal stage of AD, and is associated with accelerated disease progression. While microglia, the brain’s resident macrophages are well established as central mediators of immune responses in the central nervous system and key players in AD pathogenesis, the contribution of infiltrating myeloid cells, particularly monocytes, remains controversial. In this review, we synthesize evidence from clinical studies analyzing monocytes in peripheral blood, cerebrospinal fluid, and post-mortem brain tissue of AD patients, together with findings from preclinical mouse models of amyloid-βand tau pathology, to clarify the heterogeneity and dual roles, both detrimental and harmful of monocytes in AD progression and neuropathology.