Aβ42寡聚体对突触内外谷氨酸受体表达的影响OA北大核心CSTPCD

AIM:To explore the expression and distribution of synaptic and extrasynaptic glutamate receptors under the action of amyloid β-protein 42 oligomers(Aβ42Os)in Alzheimer disease.METHODS:In vitro,primary neu-rons from neonatal mice were treated with different concentrations of Aβ42Os.In vivo,Aβ42Os were stereotaxically injected into the lateral ventricle of C57BL/6 mice.Western blot was used to detect the protein levels of metabotropic gultamate re-ceptor 5(mGluR5)and N-methyl-D-aspartate receptor(NMDAR)subunits(NR2A,NR2B and NR1)in mouse primary neurons and mice.Immunofluorescence staining was performed to observe the distribution of mGluR5 and NMDAR.Addi-tionally,Western blot was employed to examine the expression of mGluR5 downstream phosphatidylinositol 3-kinase(PI3K)/protein kinase B(PKB/AKT)signaling pathway-related proteins,calcium signaling pathway-related proteins and synapse-related proteins in mouse hippocampal tissues.RESULTS:(1)High concentrations of Aβ42Os increased mGluR5 expression in mouse primary neurons,but reduced the expression of NR2A,NR2B and NR1(P<0.01).Treatment of pri-mary neurons with high concentration of Aβ42Os resulted in aggregation of mGluR5 on the membrane surface,and re-duced the expression of NR2A,NR2B and NR1 on the membrane surface.(2)High concentration of Aβ42Os increased the expression of synaptic mGluR5 in mouse hippocampal tissues(P<0.01),but reduced the expression of synaptic NR2A(P<0.05)and NR2B(P<0.01)and increased the expression of extrasynaptic NR2B(P<0.01).High concentration of Aβ42Os inhibited the expression of PI3K and the phosphorylation of AKT and extracellular signal-regulated kinase(ERK),and overactivated calcium/calmodulin-dependent protein kinase IIα(CaMKIIα).High concentration of Aβ42 decreased the expression of postsynaptic density protein 95,spinophilin,synaptophysin and microtubule-associated protein 2(P<0.01).CONCLUSION:(1)High concentrations of Aβ42Os increase mGluR5 expression and decrease NR2A,NR2B and NR1 expression in synapse,along with an increase in extrasynaptic NR2B.(2)High concentrations of Aβ42Os inhibit the PI3K/AKT and ERK signaling pathways,overactivated the CaMKIIα pathway,and destroyed the synaptic structures.