Department of Radiology, West China Hospital, Sichuan University, China.
The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, China.
Exp Gerontol. 2019 Oct 1;125:110660. doi: 10.1016/j.exger.2019.110660. Epub 2019 Jul 15.
Although immunoglobulin G Fc receptors with immunoreceptor tyrosine-based activation motifs (ITAM-FcγRs) have been implicated in the mediation of inflammatory responses, the importance of these receptors in the pathogenesis of cognitive impairment in geriatric diabetes remains unclear. The present study investigated the potential role of ITAM-FcγRs in cognitive impairment in geriatric diabetes.
Diabetes was induced by streptozotocin (STZ) in aged Wistar rats, and cognitive function and cerebral injury were assessed 8 weeks later using the Morris water maze (MWM), real-time PCR and Western blot. In vitro, the inhibition of ITAM-FcγRs was investigated using rat chromaffin cells cultured with high glucose.
Aged rats with diabetes exhibited marked and persistent learning and memory impairments. Enhanced cerebral inflammation in the diabetic aged rats was associated with the overactivation of the nuclear factor κB (NF-κB) signaling pathway and the upregulation of inflammatory cytokines (interleukin-6 (IL-6) and tumor nuclear factor-α (TNF-α)) in the hippocampus. Compared to no treatment, the knockdown of FcγRIV (the main isoform of ITAM-FcγRs) markedly attenuated cognitive impairment as well as histologic and ultrastructural pathologic changes in the diabetic rats. The increased expression of inflammatory cytokines and the overactivation of the NF-κB signaling pathway were also significantly alleviated. In vitro, high glucose concentrations significantly activated the NF-κB signaling pathway and increased the expression of inflammatory cytokines. The inhibition of FcγR expression by a small interfering RNA and/or a FcγRI- and FcγRIII-neutralizing antibody significantly ameliorated the effects mediated by high glucose.
The enhanced activation of the NF-κB signalling pathway may be the mechanism by which ITAM-FcγRs promote cerebral inflammation and cognitive impairment in diabetes. ITAM-FcγRs may be viewed as a potential target for preventative intervention for cognitive impairment in older adults with diabetes.
尽管免疫球蛋白 G Fc 受体（含免疫受体酪氨酸激活基序）已被认为参与了炎症反应的介导，但这些受体在老年糖尿病认知障碍发病机制中的重要性尚不清楚。本研究旨在探讨 ITAM-FcγRs 在老年糖尿病认知障碍中的潜在作用。
链脲佐菌素（STZ）诱导老年 Wistar 大鼠糖尿病，8 周后使用 Morris 水迷宫（MWM）、实时 PCR 和 Western blot 评估认知功能和脑损伤。体外，采用高糖培养的大鼠嗜铬细胞瘤研究 ITAM-FcγRs 的抑制作用。
糖尿病老年大鼠表现出明显且持久的学习和记忆障碍。糖尿病老年大鼠的大脑炎症增强与核因子 κB（NF-κB）信号通路的过度激活以及海马中炎症细胞因子（白细胞介素-6（IL-6）和肿瘤核因子-α（TNF-α））的上调有关。与未治疗组相比，FcγRIV（ITAM-FcγRs 的主要同工型）的敲低明显改善了糖尿病大鼠的认知障碍以及组织学和超微结构病理变化。炎症细胞因子的表达增加和 NF-κB 信号通路的过度激活也得到显著缓解。体外研究表明，高葡萄糖浓度显著激活 NF-κB 信号通路并增加炎症细胞因子的表达。通过小干扰 RNA 和/或 FcγRI 和 FcγRIII 中和抗体抑制 FcγR 表达，显著改善了高葡萄糖介导的作用。
NF-κB 信号通路的增强激活可能是 ITAM-FcγRs 促进糖尿病大脑炎症和认知障碍的机制。ITAM-FcγRs 可能成为预防老年糖尿病患者认知障碍的潜在靶点。
