Department of Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, The University of British Columbia, Vancouver BC, V6T1Z3, Canada.
Curr Alzheimer Res. 2020;17(12):1057-1064. doi: 10.2174/1567205018666210119143817.
The dysregulation of calcium signaling mechanisms in neurons has been considered a contributing factor to the pathogenesis evident in early-onset Alzheimer's Disease (AD). However, considerably less is known concerning the possible impairment of Ca mobilization in resident immune cell microglia. This review considers findings which suggest that a prominent pathway for non-excitable microglial cells, store-operated calcium entry (SOCE), is altered in the sporadic form of AD. The patterns of Ca mobilization are first discussed with platelet-activating factor (PAF) stimulation of SOCE in adult, fetal and immortalized cell-line, human microglia in the healthy brain. In all cases, PAF was found to induce a rapid transient depletion of Ca from endoplasmic reticulum (ER) stores, followed by a sustained entry of Ca (SOCE). A considerably attenuated duration of SOCE is observed with ATP stimulation of human microglia, suggested as due to agonist actions on differential subtype purinergic receptors. Microglia obtained from AD brain tissue, or microglia treated with full-length amyloid-β peptide (Aβ), show significant reductions in the amplitude of SOCE relative to controls. In addition, AD brain and Aβ-treated microglia exhibit decreased levels of Ca release from ER stores compared to controls. Changes in properties of SOCE in microglia could lead to altered immune cell response and neurovascular unit dysfunction in the inflamed AD brain.
神经元中钙信号机制的失调被认为是早发性阿尔茨海默病（AD）发病机制的一个促成因素。然而，关于驻留免疫细胞小胶质细胞中钙动员可能受损的情况知之甚少。这篇综述考虑了以下发现：非兴奋性小胶质细胞的一个突出途径——储存操作钙进入（SOCE），在散发性 AD 中发生改变。首先讨论了在健康大脑中，血小板激活因子（PAF）刺激成年、胎儿和永生化细胞系人小胶质细胞中的 SOCE 时的钙动员模式。在所有情况下，都发现 PAF 诱导内质网（ER）储存中钙的快速短暂耗竭，随后是钙的持续进入（SOCE）。用 ATP 刺激人小胶质细胞时，观察到 SOCE 的持续时间明显缩短，这被认为是由于激动剂对不同亚型嘌呤能受体的作用。与对照组相比，从 AD 脑组织中获得的小胶质细胞或用全长淀粉样β肽（Aβ）处理的小胶质细胞，SOCE 的幅度明显降低。此外，与对照组相比，AD 脑组织和 Aβ 处理的小胶质细胞中 ER 储存中钙的释放水平降低。小胶质细胞中 SOCE 的特性变化可能导致在炎症 AD 大脑中免疫细胞反应和神经血管单元功能障碍。
