Background: Chronic inflammation is a feature of Alzheimer´s disease (AD), resulting in excessive production of inflammatory mediators that can lead to neuroinflammation, contributing to alterations in Aβ production and deposition as Senile Plaques (SPs), and to neurofibrillary tangles (NFTs) formation, due to hyperphosphorylated Tau protein.

Objective: This work addressed the impact of the interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1), two chemokines, on Tau phosphorylation; and also evaluated the chemokines’ levels in plasma using samples from a regional cohort.

Methods: Human neuronal SH-SY5Y cells exposed to IL-8 and MCP-1 chemokines were monitored for their protein and phosphorylated protein levels by western blotting analysis. A serine/threonine protein phosphatase (PPs) activity assay was employed to monitor PPs activity. Subsequently, flow cytometry was used to monitor chemokines levels in plasma samples from individuals with cognitive deficits.

Results: Chemokines’ exposure resulted only in minor cytotoxicity effects on SH-SY5Y, and in increased Tau phosphorylation, particularly at the S396 residue. Tau phosphorylation correlated with PPs inhibition and was consistent with GSK3β phosphorylation-mediated inhibition. Subsequent analysis of plasma from individuals with cognitive deficits showed that IL-8 levels were decreased.

Conclusion: Data shows that both chemokines tested can exert an effect on GSK3β phosphorylation and modulate PPs activity, potentially resulting in increased Tau phosphorylation and subsequent NFTs formation. One can deduce that increased chemokines stimulation during chronic inflammation can exacerbate this event. The work contributes to a better understanding of the mode of action of these chemokines on AD pathogenesis and opens novel research avenues.

背景：慢性炎症是阿尔茨海默病 (AD) 的一个特征，导致炎症介质的过度产生，可导致神经炎症，导致 Aβ 产生和沉积的改变，如老年斑 (SP) 和神经原纤维缠结 (NFT) ) 形成，由于过度磷酸化的 Tau 蛋白。

目的：这项工作解决了白细胞介素 8 (IL-8) 和单核细胞趋化蛋白 1 (MCP-1) 这两种趋化因子对 Tau 磷酸化的影响；并且还使用来自区域队列的样本评估了血浆中趋化因子的水平。

方法：通过蛋白质印迹分析监测暴露于 IL-8 和 MCP-1 趋化因子的人神经元 SH-SY5Y 细胞的蛋白质和磷酸化蛋白质水平。采用丝氨酸/苏氨酸蛋白磷酸酶 (PPs) 活性测定来监测 PPs 活性。随后，流式细胞术用于监测来自认知缺陷个体的血浆样品中的趋化因子水平。

结果：趋化因子的暴露仅导致对 SH-SY5Y 的轻微细胞毒性影响，并导致 Tau 磷酸化增加，尤其是在 S396 残基处。Tau 磷酸化与 PP 抑制相关，并且与 GSK3β 磷酸化介导的抑制一致。随后对认知缺陷患者血浆的分析表明 IL-8 水平降低。

结论：数据表明，测试的两种趋化因子都可以对 GSK3β 磷酸化产生影响并调节 PP 活性，可能导致 Tau 磷酸化增加和随后的 NFT 形成。可以推断，慢性炎症期间增加的趋化因子刺激会加剧这一事件。这项工作有助于更好地了解这些趋化因子对 AD 发病机制的作用模式，并开辟了新的研究途径。