Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Bvld, Tampa, FL, 33612, USA.
J Neuroinflammation. 2019 Feb 11;16(1):30. doi: 10.1186/s12974-019-1412-9.
Alzheimer's disease (AD) is a progressive, neurodegenerative disorder, and the most common form of dementia. As the understanding of AD has progressed, it is now believed that AD is an amyloid-initiated tauopathy with neuroinflammation serving as the link between amyloid deposition, tau pathology, and neurodegeneration. As microglia are the main immune effectors in the central nervous system, they have been the focus of attention in studies investigating the neuroinflammatory component of AD. Therefore, recent work has focused on immunomodulators, which can alter microglial activation without suppressing activity, as potential therapeutics for AD. Fractalkine (CX3CL1; FKN), a unique chemokine with a one-to-one relationship with its receptor, signals through its cognate receptor (CX3CR1) to reduce expression of pro-inflammatory genes in activated microglia. Disrupting FKN signaling has opposing effects on the two hallmark pathologies of AD, but over-expressing a soluble FKN has been shown to reduce tau pathology while not altering amyloid pathology. Recently, differential signaling has been reported when comparing two cleavage variants of soluble FKN. These differential effects may explain recent studies reporting seemingly conflicting results regarding the effect of FKN over expression on AD pathologies.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，也是最常见的痴呆症形式。随着对 AD 的认识不断深入，现在人们认为 AD 是一种淀粉样蛋白起始的 tau 病，神经炎症是淀粉样蛋白沉积、tau 病理学和神经退行性变之间的联系。由于小胶质细胞是中枢神经系统中的主要免疫效应细胞，因此它们一直是研究 AD 神经炎症成分的焦点。因此，最近的工作集中在免疫调节剂上，这些调节剂可以改变小胶质细胞的激活而不抑制其活性，作为 AD 的潜在治疗方法。趋化因子（CX3CL1；FKN）是一种独特的趋化因子，与受体呈一对一关系，通过其同源受体（CX3CR1）发出信号，减少激活的小胶质细胞中促炎基因的表达。破坏 FKN 信号对 AD 的两种标志性病理学有相反的影响，但过表达可溶性 FKN 已被证明可减少 tau 病理学，而不改变淀粉样蛋白病理学。最近，在比较可溶性 FKN 的两种裂解变体时，报告了不同的信号转导。这些差异效应可能解释了最近的研究报告，即 FKN 过表达对 AD 病理学的影响似乎存在矛盾。
