Biochemistry and Molecular Biology Unit, Department of Biomedical Sciences, Faculty of Medicine-IDIBAPS, University of Barcelona, Barcelona, Spain.
Neurological Tissue Bank of the Biobank, Hospital Clinic, IDIBAPS, Barcelona, Spain.
Mol Neurobiol. 2018 Mar;55(3):2340-2349. doi: 10.1007/s12035-017-0489-3. Epub 2017 Mar 25.
Neuroinflammation and microglial dysfunction have a prominent role in the pathogenesis of late-onset Alzheimer's disease (LOAD). CX3CR1 is a microglia-specific gene involved in microglia-neuron crosstalk and neuroinflammation. Numerous evidence show the involvement of CX3CR1 in AD. The aim of this study was to investigate if some functional genetic variants of this gene could influence on LOAD's outcome, in a neuropathologically confirmed Spanish cohort. We designed an open, pragmatic, case-control retrospective study including a total of 475 subjects (205 pathologically confirmed AD cases and 270 controls). We analyzed the association of the two CX3CR1 functional variants (V249I, rs3732379; and T280M, rs3732378) with neurofibrillary pathology progression rate according to Braak's staging system, age at onset (AAO), survival time, and risk of suffering LOAD. We found that individuals heterozygous for CX3CR1-V249I presented a lower neurofibrillary pathology stage at death (OR = 0.42, 95%CI [0.23, 0.74], p = 0.003, adj-p = 0.013) than the other genotypes. Eighty percent of the subjects homozygous for 249I had higher neurofibrillary pathology progression (Braak's stage VI). Moreover, homozygosis for 280M and 249I could be associated with a higher AAO in the subgroups of AD with Lewy bodies and without Lewy bodies. These CX3CR1 genetic variants could represent new modifying factors of pathology progression and age at onset in LOAD. These results provide further evidence of the involvement of CX3CR1 pathway and microglia/macrophages in the pathogenesis of LOAD.
神经炎症和小胶质细胞功能障碍在晚发性阿尔茨海默病（LOAD）的发病机制中起重要作用。CX3CR1 是一种与小胶质细胞-神经元相互作用和神经炎症有关的小胶质细胞特异性基因。大量证据表明 CX3CR1 参与了 AD 的发生。本研究旨在调查该基因的一些功能性遗传变异是否会影响西班牙神经病理学确诊队列中 LOAD 的结局。我们设计了一项开放、实用、病例对照的回顾性研究，共纳入 475 名受试者（205 例经病理学证实的 AD 病例和 270 例对照）。我们分析了两个 CX3CR1 功能变体（V249I，rs3732379；和 T280M，rs3732378）与根据 Braak 分期系统、发病年龄（AAO）、生存时间和 LOAD 发病风险的神经纤维病理进展率之间的关联。我们发现，CX3CR1-V249I 杂合子个体在死亡时的神经纤维病理分期较低（OR=0.42，95%CI[0.23，0.74]，p=0.003，adj-p=0.013），而其他基因型则较高。80%的 249I 纯合子患者的神经纤维病理进展（Braak 分期 VI）较高。此外，280M 和 249I 的纯合性可能与路易体 AD 亚组和无路易体 AD 亚组的较高 AAO 相关。这些 CX3CR1 遗传变异可能是 LOAD 中病理进展和发病年龄的新修饰因素。这些结果为 CX3CR1 通路和小胶质细胞/巨噬细胞在 LOAD 发病机制中的作用提供了进一步证据。
