Impairments Of Amyloid β-protein On Synaptic Plasticity

ObjectiveAbnormal synaptic plasticity (especially abnormal hippocampal synaptic plasticity) is considered to be the main cause of cognition, learning and memory dysfunction. Research on synaptic plasticity is helpful to reveal the pathological mechanism of mental retardation, cognitive dysfunction and other mental diseases. Although synaptic plasticity has been intensively investigated, the underlying mechanism of synaptic plasticity is not clear, need further study.The amyloid-β protein(Aβ)-induced impairments in synaptic plasticity coincide with memory decline and dementia. Although numerous studies have been done about soluble Aβ oligomers induced abnormal synaptic plasticity, but the deep mechanism remains unclear.Intracellular Ca2+ homeostasis is vital in regulating synaptic plasticity. The Ca2+ overload process a series of adverse effects on synaptic structure and function, neuronal physiology, and memory formation.2-aminoethoxydiphenyl borate (2-APB) is a non-specific but moderately potent membrane-permeable modulator with inhibitory actions on multiple targets including IP3R, RyR, SOCE, TRP et, al. Gensingnoside Rg3 can antagonize Ca2+ influx. This study investigated role of 2-APB and Gensingnoside Rg3 on Aβ induced synaptic plasticity impairments.MethodsC57BL/6 wildtype mice and amyloid precursor protein/presenilin 1(APPswe/PS1 ΔE9) gene mutant/wildtype mice were used to study.Hippocampal slices were used in electrophysiological recording. The input-output (I/O) curve, PTP and LTP/LTD were recorded to investigate the effect of Aβ and other drugs on synaptic plasticity.Membrane protein and total protein were extracted to investigate the effect of Aβ and other drugs on AMPA receptor phosphorylation, trafficking and BAX, caspase-3, cleaved caspase-3, GSK3, p-GSK3, GluRl, p-GluRl, NR2B, NR2A, Cytc expression. Culture hippocampal neuron, investigate the effect of Aβ and other drugs on Ca2+, caspase-3, cleaved caspase-3, GSK3, p-GSK3, Mitochondria, Cytc, IP3R and dendritic spines.APP/PS1 and WT were intragastric administrated with Gensingnoside Rg3 or CMC-Na for 3 months at 3 months. Drug treated and vehicle-treated APP/PS1 and WT mice were killed at 8 and 16 months for Golgi Staining.ResultsAβ did not obviously alter basal synaptic neurotransmission, but dramatically induces short-term and long-term synaptic plasticity deficit in hippocampal slices.2-APB can prevent these suppression in a dose dependent. Caspase-3 inhibition contributed to the protective effect of 2-APB on LTP. Aβ facilitate hippocampal LTD and this effect can be reversed by Gensingnoside Rg3. 2-APB can restore Aβ-mediated disruptive effect on AMPA receptor trafficking, reduce Aβ elevation of neuronal intracellular Ca2+, block Ap activation of caspase 3/GSK3β signaling and Aβ stimulation of cytochrome c release from mitochondria, reverse Aβ induced BAX transactivation.2-APB can rescue hippocampal LTP deficit in APP swe/PS1ΔE9 gene mutant mice. Gensingnoside Rg3 can protect Aβ induced neuron spines lose and dendritic spines pathology in APP/PS1 mice.ConclusionsAβ-induced impairments in synaptic plasticity may be related to the elevation of intracellular calcium and, the effect involves caspase-3, GSK3, Cytc, BAX activation. 2-APB and Rg3 can protect Aβ-induced synaptic dysfunctions.