Department of Physiology, Faculty of Medicine, CIBERFES, Fundación Investigación Hospital Clínico Universitario/INCLIVA, University of Valencia, Valencia, Spain.
Department of Physiology, Faculty of Medicine, CIBERFES, Fundación Investigación Hospital Clínico Universitario/INCLIVA, University of Valencia, Valencia, Spain; Internal Medicine Department, University Hospital of La Plana, Vila-Real, Spain.
Free Radic Biol Med. 2024 Mar;215:56-63. doi: 10.1016/j.freeradbiomed.2024.02.021. Epub 2024 Feb 27.
Carrying an allele 4 of the apolipoprotein E (ApoE) is the best-established genetic risk factor to develop Alzheimer's disease (AD). Fifty percent of ApoE4/4 individuals develop the disease at 70 years of age. ApoE3/4 carriers have a lower risk of developing the disease, still 50% of them suffer AD at around 80 years. In a previous study we showed that healthy young individuals, who had a parent with AD and were carriers of at least one ApoE4 allele displayed reductive stress. This was evidenced as a decrease in oxidative markers, such as oxidized glutathione, p-p38, and NADP/NADPH ratio, and an increase of antioxidant enzymes, such as glutathione peroxidase (Gpx1) and both the catalytic and regulatory subunits of glutamyl-cysteinyl (GCLM and GCLC). Moreover, we found an increase in stress-related proteins involved in tau physiopathology. Now, 10 years later, we have conducted a follow-up study measuring the same parameters in the same cohort. Our results show that reductive stress has reversed, as we could now observe an increase in lipid peroxidation and in the oxidation of glutathione along with a decrease in the expression of Gpx1 and SOD1 antioxidant enzymes in ApoE4 carriers. Furthermore, we found an increase in plasma levels of IL1β levels and in PKR (eukaryotic translation initiation factor 2 alpha kinase 2) gene expression in isolated lymphocytes. Altogether, our results suggest that, in the continuum of Alzheimer's disease, people at risk of developing the disease go through different redox phases, from stablished reductive stress to oxidative stress.
携带载脂蛋白 E（ApoE）的等位基因 4 是阿尔茨海默病（AD）发生的最佳遗传风险因素。50%的 ApoE4/4 个体在 70 岁时发病。ApoE3/4 携带者发病风险较低，但仍有 50%的人在 80 岁左右患有 AD。在之前的一项研究中，我们发现携带至少一个 ApoE4 等位基因的健康年轻个体，其父母患有 AD，表现出还原性应激。这表现为氧化标志物如氧化型谷胱甘肽、p-p38 和 NADP/NADPH 比值降低，以及抗氧化酶如谷胱甘肽过氧化物酶（Gpx1）和谷氨酰半胱氨酸（GCLM 和 GCLC）的催化和调节亚基增加。此外，我们还发现与 tau 病理生理学相关的应激相关蛋白增加。现在，10 年后，我们对同一队列进行了后续研究，测量了相同的参数。我们的研究结果表明，还原性应激已经逆转，因为我们现在可以观察到 ApoE4 携带者的脂质过氧化和谷胱甘肽氧化增加，同时抗氧化酶 Gpx1 和 SOD1 的表达减少。此外，我们发现分离淋巴细胞中的白细胞介素 1β 水平和 PKR（真核翻译起始因子 2 阿尔法激酶 2）基因表达增加。总的来说，我们的研究结果表明，在阿尔茨海默病的连续体中，有发病风险的人经历了不同的氧化还原阶段，从已建立的还原性应激到氧化应激。
