INTRODUCTIONTo investigate the role of a novel type of protein kinase C delta (PKCδ) in the neuroinflammation of Alzheimer's disease (AD).METHODSWe analyzed PKCδ and inflammatory cytokines levels in cerebrospinal fluid (CSF) of AD and normal controls, as well as their correlations. The cellular expression pattern of PKCδ and the effects of PKCδ modulation on microglia‐mediated neuroinflammation were evaluated by quantitative real‐time polymerase chain reaction (qRT‐PCR), western blot, RNA sequencing (RNA‐seq), and immunofluorescence staining.RESULTSPKCδ levels were increased dramatically in the CSF of AD patients and positively correlated with cytokines. PKCδ is expressed mainly in microglia in the brain. Amyloid beta (Aβ) stimulation increased PKCδ expression and secretion, which led to upregulation of the nuclear factor kappa B (NF‐κB) pathway and overproduction of proinflammatory cytokines. Downregulation or inhibition of PKCδ attenuated Aβ‐induced microglial responses and improved cognitive function in an AD mouse model.DISCUSSIONOur study identifies PKCδ as a potential biomarker and therapeutic target for microglia‐mediated neuroinflammation in AD.Highlights Protein kinase C delta (PKCδ) levels increase in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD), and positively correlate with elevated inflammatory cytokines in human subjects. PKCδ is expressed mainly in microglia in vivo, whereas amyloid beta (Aβ) stimulation increases PKCδ expression and secretion, causing upregulation of the nuclear factor kappa B (NF‐κB) pathway and production of inflammatory cytokines. Downregulation or inhibition of PKCδ attenuates Aβ‐enhanced NF‐κB signaling and cytokine production in microglia and improves cognitive function in AD mice. PKCδ serves as a potential biomarker and therapeutic target for microglia‐mediated neuroinflammation in AD.

中文翻译：

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PKCδ 是阿尔茨海默病中小胶质细胞介导的神经炎症的潜在生物标志物和治疗靶点


引言探讨新型蛋白激酶Cδ（PKCδ）在阿尔茨海默病（AD）神经炎症中的作用。方法分析AD和正常对照脑脊液（CSF）中PKCδ和炎症细胞因子的水平及其相关性。通过定量实时聚合酶链反应 (qRT-PCR)、蛋白质印迹、RNA 测序 (RNA-seq) 和免疫荧光染色评估 PKCδ 的细胞表达模式以及 PKCδ 调节对小胶质细胞介导的神经炎症的影响。 结果 PKCδ 水平AD 患者脑脊液中显着增加，且与细胞因子呈正相关。 PKCδ 主要在大脑中的小胶质细胞中表达。 β 淀粉样蛋白 (Aβ) 刺激增加 PKCδ 表达和分泌，从而导致核因子 kappa B (NF-κB) 通路上调和促炎细胞因子过量产生。下调或抑制 PKCδ 可减弱 Aβ 诱导的小胶质细胞反应并改善 AD 小鼠模型中的认知功能。讨论我们的研究将 PKCδ 确定为 AD 中小胶质细胞介导的神经炎症的潜在生物标志物和治疗靶点。亮点蛋白激酶 C δ (PKCδ) 水平增加阿尔茨海默氏病 (AD) 患者的脑脊液 (CSF) 中存在这种水平，并且与人类受试者中炎症细胞因子的升高呈正相关。 PKCδ 主要在体内小胶质细胞中表达，而β淀粉样蛋白 (Aβ) 刺激会增加 PKCδ 表达和分泌，导致核因子 kappa B (NF-κB) 通路上调和炎症细胞因子的产生。下调或抑制 PKCδ 会减弱小胶质细胞中 Aβ 增强的 NF-κB 信号传导和细胞因子的产生，并改善 AD 小鼠的认知功能。 PKCδ 是 AD 中小胶质细胞介导的神经炎症的潜在生物标志物和治疗靶点。