Amyloid Aβ<sub>25-35</sub> Aggregates Say ‘NO’ to Long-Term Potentiation in the Hippocampus through Activation of Stress-Induced Phosphatase 1 and Mitochondrial Na<sup>+</sup>/Ca<sup>2+</sup> Exchanger
The search for strategies for strengthening the synaptic efficiency in Aβ<sub>25-35</sub>-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, me...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-10-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/19/11848 |
| Summary: | The search for strategies for strengthening the synaptic efficiency in Aβ<sub>25-35</sub>-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<sub>25-35</sub>-associated signaling in the hippocampus. Aβ<sub>25-35</sub> 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<sub>25-35</sub>-dependent LTP suppression for both simultaneous and delayed enzyme blockade protocols. STPP activity in the Aβ<sub>25-35</sub>-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<sub>25-35</sub>-mediated LTP suppression prevention. A mitochondrial Na<sup>+</sup>/Ca<sup>2+</sup> exchanger (mNCX) blocker, CGP37157, also attenuated the Aβ<sub>25-35</sub>-induced LTP decline. Aβ<sub>25-35</sub> aggregates did not change the mitochondrial transmembrane potential or reactive oxygen species (ROS) production but affected the ion transport and Ca<sup>2+</sup>-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<sub>25-35</sub>-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<sub>25-35</sub>-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<sub>25-35</sub>-driven deteriorations. |
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| ISSN: | 1661-6596 1422-0067 |