Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, Butlerova 5A, 117485 Moscow, Russia.
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, Pushchino, 142290 Moscow, Russia.
Int J Mol Sci. 2022 Oct 6;23(19):11848. doi: 10.3390/ijms231911848.
The search for strategies for strengthening the synaptic efficiency in Aβ-treated slices is a challenge for the compensation of amyloidosis-related pathologies. Here, we used the recording of field excitatory postsynaptic potentials (fEPSPs), nitric oxide (NO) imaging, measurements of serine/threonine protein phosphatase (STPP) activity, and the detection of the functional mitochondrial parameters in suspension of brain mitochondria to study the Aβ-associated signaling in the hippocampus. Aβ aggregates shifted the kinase-phosphatase balance during the long-term potentiation (LTP) induction in the enhancement of STPP activity. The PP1/PP2A inhibitor, okadaic acid, but not the PP2B blocker, cyclosporin A, prevented Aβ-dependent LTP suppression for both simultaneous and delayed enzyme blockade protocols. STPP activity in the Aβ-treated slices was upregulated, which is reverted relative to the control values in the presence of PP1/PP2A but not in the presence of the PP2B blocker. A selective inhibitor of stress-induced PP1α, sephin1, but not of the PP2A blocker, cantharidin, is crucial for Aβ-mediated LTP suppression prevention. A mitochondrial Na/Ca exchanger (mNCX) blocker, CGP37157, also attenuated the Aβ-induced LTP decline. Aβ aggregates did not change the mitochondrial transmembrane potential or reactive oxygen species (ROS) production but affected the ion transport and Ca-dependent swelling of organelles. The staining of hippocampal slices with NO-sensitive fluorescence dye, DAF-FM, showed stimulation of the NO production in the Aβ-pretreated slices at the dendrite-containing regions of CA1 and CA3, in the dentate gyrus (DG), and in the CA1/DG somata. NO scavenger, PTIO, or nNOS blockade by selective inhibitor 3Br-7NI partly restored the Aβ-induced LTP decline. Thus, hippocampal NO production could be another marker for the impairment of synaptic plasticity in amyloidosis-related states, and kinase-phosphatase balance management could be a promising strategy for the compensation of Aβ-driven deteriorations.
寻找增强 Aβ 处理切片中突触效率的策略是补偿淀粉样变性相关病理学的挑战。在这里，我们使用场兴奋性突触后电位 (fEPSP) 的记录、一氧化氮 (NO) 成像、丝氨酸/苏氨酸蛋白磷酸酶 (STPP) 活性测量以及悬浮脑线粒体中的功能线粒体参数检测来研究海马体中的 Aβ 相关信号。Aβ 聚集物在长时程增强 (LTP) 诱导过程中改变了激酶-磷酸酶平衡，增强了 STPP 活性。PP1/PP2A 抑制剂 okadaic 酸，但不是 PP2B 阻断剂环孢菌素 A，可防止 Aβ 依赖性 LTP 抑制，无论是同时还是延迟酶阻断方案。Aβ 处理切片中的 STPP 活性上调，与对照值相比，在存在 PP1/PP2A 的情况下相对逆转，但在存在 PP2B 阻断剂的情况下则不然。应激诱导的 PP1α 选择性抑制剂 sephin1 但不是 PP2A 阻断剂 cantharidin 对 Aβ 介导的 LTP 抑制预防至关重要。线粒体 Na/Ca 交换器 (mNCX) 阻断剂 CGP37157 也减弱了 Aβ 诱导的 LTP 下降。Aβ 聚集物不会改变线粒体跨膜电位或活性氧 (ROS) 产生，但会影响离子转运和细胞器的 Ca 依赖性肿胀。用 NO 敏感荧光染料 DAF-FM 对海马切片进行染色显示，在 Aβ 预处理切片的 CA1 和 CA3 的包含树突的区域、齿状回 (DG) 和 CA1/DG 体中，NO 产生增加。NO 清除剂 PTIO 或选择性抑制剂 3Br-7NI 对 nNOS 的阻断部分恢复了 Aβ 诱导的 LTP 下降。因此，海马体 NO 产生可能是淀粉样变性相关状态下突触可塑性受损的另一个标志物，激酶-磷酸酶平衡管理可能是补偿 Aβ 驱动恶化的有前途的策略。
