Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy.
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, Ed. 16, 90128 Palermo, Italy.
Int J Mol Sci. 2023 May 4;24(9):8230. doi: 10.3390/ijms24098230.
Alzheimer's disease (AD) is a scourge for patients, caregivers and healthcare professionals due to the progressive character of the disease and the lack of effective treatments. AD is considered a proteinopathy, which means that aetiological and clinical features of AD have been linked to the deposition of amyloid β (Aβ) and hyperphosphorylated tau protein aggregates throughout the brain, with Aβ and hyperphosphorylated tau representing classical AD hallmarks. However, some other putative mechanisms underlying the pathogenesis of the disease have been proposed, including inflammation in the brain, microglia activation, impaired hippocampus neurogenesis and alterations in the production and release of neurotrophic factors. Among all, microglia activation and chronic inflammation in the brain gained some attention, with researchers worldwide wondering whether it is possible to prevent and stop, respectively, the onset and progression of the disease by modulating microglia phenotypes. The following key points have been established so far: (i) Aβ deposition in brain parenchyma represents repeated stimulus determining chronic activation of microglia; (ii) chronic activation and priming of microglia make these cells lose neuroprotective functions and favour damage and loss of neurons; (iii) quiescent status of microglia at baseline prevents chronic activation and priming, meaning that the more microglia are quiescent, the less they become neurotoxic. Many molecules are known to modulate the quiescent baseline state of microglia, attracting huge interest among scientists as to whether these molecules could be used as valuable targets in AD treatment. The downside of the coin came early with the observation that quiescent microglia do not display phagocytic ability, being unable to clear Aβ deposits since phagocytosis is crucial for Aβ clearance efficacy. A possible solution for this issue could be found in the modulation of microglia status at baseline, which could help maintain both neuroprotective features and phagocytic ability at the same time. Among the molecules known to influence the baseline status of microglia, C-X3-chemokine Ligand 1 (CX3CL1), also known as Fractalkine (FKN), is one of the most investigated. FKN and its microglial receptor CX3CR1 are crucial players in the interplay between neurons and microglia, modulating the operation of some neural circuits and the efficacy and persistence of immune response against injury. In addition, CX3CL1 regulates synaptic pruning and plasticity in the developmental age and in adulthood, when it strongly impacts the hippocampus neurogenesis of the adult. CX3CL1 has an effect on Aβ clearance and tau phosphorylation, as well as in microglia activation and priming. For all the above, CX3CL1/CX3CR1 signalling has been widely studied in relation to AD pathogenesis, and its biochemical pathway could hide molecular targets for novel treatment strategies in AD. This review summarizes the possible role of CX3CL1 in AD pathogenesis and its use as a potential target for AD treatment.
阿尔茨海默病（AD）是一种对患者、护理人员和医疗保健专业人员的祸害，因为疾病的进展性和缺乏有效治疗方法。AD 被认为是一种蛋白质病，这意味着 AD 的病因和临床特征与大脑中淀粉样 β（Aβ）和过度磷酸化的 tau 蛋白聚集体的沉积有关，Aβ 和过度磷酸化的 tau 代表了经典的 AD 标志物。然而，已经提出了一些其他潜在的疾病发病机制，包括大脑中的炎症、小胶质细胞激活、海马神经发生受损以及神经营养因子的产生和释放改变。在所有这些机制中，小胶质细胞激活和大脑中的慢性炎症引起了人们的关注，世界各地的研究人员都想知道是否可以通过调节小胶质细胞表型来预防和阻止疾病的发作和进展。到目前为止，已经确定了以下关键点：（i）脑实质中的 Aβ 沉积代表了决定小胶质细胞慢性激活的反复刺激；（ii）小胶质细胞的慢性激活和启动使其失去神经保护功能，并有利于神经元的损伤和丢失；（iii）小胶质细胞在基线时的静止状态可防止慢性激活和启动，这意味着小胶质细胞越静止，它们的神经毒性就越低。有许多分子已知可以调节小胶质细胞的静止基线状态，这引起了科学家们的极大兴趣，他们想知道这些分子是否可以作为 AD 治疗的有价值靶点。但硬币的另一面是，早期观察到静止的小胶质细胞没有吞噬能力，这是因为吞噬作用对于 Aβ 清除效果至关重要，因此无法清除 Aβ 沉积。这个问题的一个可能解决方案可以在小胶质细胞状态的基线调节中找到，这可以帮助同时保持神经保护特征和吞噬能力。在已知影响小胶质细胞基线状态的分子中，C-X3-趋化因子配体 1（CX3CL1），也称为 fractalkine（FKN），是研究最多的分子之一。FKN 和它的小胶质细胞受体 CX3CR1 是神经元和小胶质细胞之间相互作用的关键参与者，调节一些神经回路的运作以及对损伤的免疫反应的效力和持久性。此外，CX3CL1 在发育年龄和成年期调节突触修剪和可塑性，在成年期强烈影响海马神经发生。CX3CL1 对 Aβ 清除和 tau 磷酸化以及小胶质细胞激活和启动有影响。鉴于上述所有原因，CX3CL1/CX3CR1 信号通路在 AD 发病机制中得到了广泛研究，其生化途径可能隐藏着 AD 治疗的新治疗策略的分子靶点。本综述总结了 CX3CL1 在 AD 发病机制中的可能作用及其作为 AD 治疗潜在靶点的用途。
