Department of Psychiatry, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Alzheimers Dement. 2024 Jan;20(1):124-135. doi: 10.1002/alz.13392. Epub 2023 Jul 25.
As the chemokine receptor5 (CCR5) may play a role in ischemia, we studied the links between CCR5 deficiency, the sensitivity of neurons to oxidative stress, and the development of dementia.
Logistic regression models with CCR5/apolipoprotein E (ApoE) polymorphisms were applied on a sample of 205 cognitively normal individuals and 189 dementia patients from Geneva. The impact of oxidative stress on Ccr5 expression and cell death was assessed in mice neurons.
CCR5-Δ32 allele synergized with ApoEε4 as risk factor for dementia and specifically for dementia with a vascular component. We confirmed these results in an independent cohort from Italy (157 cognitively normal and 620 dementia). Carriers of the ApoEε4/CCR5-Δ32 genotype aged ≥80 years have an 11-fold greater risk of vascular-and-mixed dementia. Oxidative stress-induced cell death in Ccr5 mice neurons.
We propose the vulnerability of CCR5-deficient neurons in response to oxidative stress as possible mechanisms contributing to dementia.
由于趋化因子受体 5（CCR5）可能在缺血中起作用，我们研究了 CCR5 缺乏、神经元对氧化应激的敏感性与痴呆症发展之间的联系。
我们在来自日内瓦的 205 名认知正常个体和 189 名痴呆症患者的样本中应用了带有 CCR5/载脂蛋白 E（ApoE）多态性的逻辑回归模型。在小鼠神经元中评估了氧化应激对 Ccr5 表达和细胞死亡的影响。
CCR5-Δ32 等位基因与 ApoEε4 协同作用，成为痴呆症的风险因素，特别是具有血管成分的痴呆症。我们在来自意大利的独立队列中证实了这些结果（157 名认知正常和 620 名痴呆症患者）。年龄≥80 岁且携带 ApoEε4/CCR5-Δ32 基因型的患者患血管性和混合性痴呆症的风险增加 11 倍。氧化应激诱导 Ccr5 小鼠神经元中的细胞死亡。
我们提出 CCR5 缺陷神经元对氧化应激的脆弱性可能是导致痴呆症的机制之一。
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