Mota Sandra I, Fão Lígia, Coelho Patrícia, Rego A Cristina
CNC-UC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal.
CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal.
Antioxidants (Basel). 2023 Sep 16;12(9):1770. doi: 10.3390/antiox12091770.
Soluble Aβ oligomers (AβO) are formed in the early stages of Alzheimer's disease (AD) and were previously shown to trigger enhanced Ca levels and mitochondrial dysfunction via the activation of -methyl-D-aspartate receptors (NMDAR). Src kinase is a ubiquitous redox-sensitive non-receptor tyrosine kinase involved in the regulation of several cellular processes, which was demonstrated to have a reciprocal interaction towards NMDAR activation. However, little is known about the early-stage mechanisms associated with AβO-induced neurodysfunction involving Src. Thus, in this work, we analysed the influence of brief exposure to oligomeric Aβ on Src activation and related mechanisms involving mitochondria and redox changes in mature primary rat hippocampal neurons. Data show that brief exposure to AβO induce HO-dependent Src activation involving different cellular events, including NMDAR activation and mediated intracellular Ca rise, enhanced cytosolic and subsequent mitochondrial HO levels, accompanied by mild mitochondrial fragmentation. Interestingly, these effects were prevented by Src inhibition, suggesting a feedforward modulation. The current study supports a relevant role for Src kinase activation in promoting the loss of postsynaptic glutamatergic synapse homeostasis involving cytosolic and mitochondrial ROS generation after brief exposure to AβO. Therefore, restoring Src activity can constitute a protective strategy for mitochondria and related hippocampal glutamatergic synapses.
可溶性淀粉样β寡聚体（AβO）在阿尔茨海默病（AD）的早期形成，先前的研究表明，它可通过激活N-甲基-D-天冬氨酸受体（NMDAR）触发细胞内钙水平升高和线粒体功能障碍。Src激酶是一种普遍存在的对氧化还原敏感的非受体酪氨酸激酶，参与多种细胞过程的调节，已证明其与NMDAR激活存在相互作用。然而，关于AβO诱导的涉及Src的神经功能障碍的早期机制知之甚少。因此，在本研究中，我们分析了短暂暴露于寡聚体Aβ对Src激活以及成熟原代大鼠海马神经元中线粒体和氧化还原变化相关机制的影响。数据显示，短暂暴露于AβO可诱导依赖血红素加氧酶（HO）的Src激活，涉及不同的细胞事件，包括NMDAR激活和介导的细胞内钙升高、胞质和随后线粒体HO水平升高，同时伴有轻度线粒体碎片化。有趣的是，这些效应可被Src抑制所阻止，提示存在前馈调节。本研究支持Src激酶激活在短暂暴露于AβO后促进突触后谷氨酸能突触稳态丧失中发挥相关作用，这涉及胞质和线粒体活性氧的产生。因此，恢复Src活性可能构成一种保护线粒体和相关海马谷氨酸能突触的策略。
