Department of Biochemistry, Basic Medical Science Block II, Sector 25, Panjab University, Chandigarh, 160014, India.
National Agri-Food Biotechnology Institute, Sector 81, S.A.S. Nagar, Mohali, Punjab, 140306, India.
Mol Neurobiol. 2018 Dec;55(12):8916-8935. doi: 10.1007/s12035-018-0985-0. Epub 2018 Apr 3.
Evidence from animal studies categorizes sporadic Alzheimer's disease (sAD) as a metabolic syndrome with accompanying cognitive deficits. Given that glial cells act as "silent partners" to neurons by providing trophic support and defense, the present study investigated the role of glia in sAD pathology. A streptozotocin (STZ)-induced glial-neuronal co-culture model of sAD was used to study the metabolic status of the two cell types. Real time RT-PCR and Western blotting results indicated that amyloid precursor protein (APP) and β-secretase (BACE1) were highly expressed in co-cultured neurons than in monocultures. Increased amyloidogenesis was accompanied by decreased expression of mediators in insulin signaling pathway that included insulin receptor (IR), insulin receptor substrate 2 (IRS2), insulin-like growth factor 2 (IGF2), insulin-like growth factor 1 receptor (IGF1R), total-glycogen synthase kinase 3β (t-GSK3β), and phosphorylated-GSK3β (p-GSK3β), suggesting that neuronal cells are more prone to metabolic variability when cultured in the presence of glial cells. Findings from the sAD model induced by intracerebroventricular (ICV) injection of STZ revealed that increased amyloid beta (Aβ) load in the hippocampus was potentially responsible for the hyperphosphorylation of tau at ser. Furthermore, impaired cognitive functions and decreased dendritic spine density and axonal thinning in CA1 region of hippocampus were associated with decreased IR and p-GSK3β/t-GSK3β expression. Taken together, the present study provides evidence that glia mediated response and insulin signaling defects drive pathological changes in sAD and represent potential targets for delaying sAD progression.
动物研究证据将散发性阿尔茨海默病（sAD）归类为伴有认知缺陷的代谢综合征。鉴于神经胶质细胞通过提供营养支持和防御作用充当神经元的“沉默伙伴”，本研究探讨了胶质细胞在 sAD 病理中的作用。使用链脲佐菌素（STZ）诱导的 sAD 胶质-神经元共培养模型研究两种细胞类型的代谢状态。实时 RT-PCR 和 Western blot 结果表明，共培养神经元中的淀粉样前体蛋白（APP）和β-分泌酶（BACE1）表达高于单培养。淀粉样生成增加伴随着胰岛素信号通路中包括胰岛素受体（IR）、胰岛素受体底物 2（IRS2）、胰岛素样生长因子 2（IGF2）、胰岛素样生长因子 1 受体（IGF1R）、总糖原合酶激酶 3β（t-GSK3β）和磷酸化-GSK3β（p-GSK3β）在内的介质表达降低，表明当神经元细胞在胶质细胞存在的情况下培养时更容易发生代谢变化。通过侧脑室（ICV）注射 STZ 诱导的 sAD 模型的研究结果表明，海马体中 Aβ负荷的增加可能是 tau 在丝氨酸处过度磷酸化的原因。此外，认知功能受损以及海马体 CA1 区树突棘密度和轴突变薄与 IR 和 p-GSK3β/t-GSK3β表达降低有关。综上所述，本研究提供的证据表明，胶质细胞介导的反应和胰岛素信号缺陷导致 sAD 的病理变化，并代表了延迟 sAD 进展的潜在靶点。
