Study On The Involvement Of CRTC1-BDNF Signaling Pathway In Synaptic Plasticity Deficits And Cognitive Dysfunction In The Early Stage Of Alzheimer’s Disease

Background: Alzheimer’s disease（AD）is a progressive neurodegenerative disease,which is characterized by progressive cognitive impairment,memory loss and changes in personality and behavior.Studies have shown that soluble β amyloid（Aβ）plays an important role in cognitive dyfunction in early AD.Neural plasticity is the neural basis of learning and memory.Long term potentiation（LTP）is a phenomenon that the synaptic transmission efficiency induced by tetanic stimulation is enhanced for a long time and closely related to the learning and memory.Late-phase LTP（L-LTP）is a synaptic model of long-term memory,requiring cAMP-responsive element binding protein（CREB）regulated cAMP-responsive element（CRE）gene transcription and new protein synthesis.Nuclear translocation of CREB-regulated transcription coactivator 1（CRTC1）may enhance the interaction of CREB with CBP/p300 via interaction with the bZIP domain of CREB,thus increase CREB-mediated transcriptional activity independently of Ser133 phosphorylation,such as brain-derived neurotrophic factor（BDNF）.The activity-dependent nuclear translocation of CRTC1 is essential for the maintenance of hippocampal L-LTP.The receptor of BDNF is tropomyosin-related kinase receptors B（TrkB）.BDNF plays an important role in neuronal development and survival,synaptic plasticity,learning and memory functions.Previous studies from our group indicate: Aβ₄₂ oligomers can cause L-LTP deficits;RNA interference CRTC1 lentivirus（LV-Sh-CRTC1）can also cause L-LTP deficits;however,the combination of LV-Sh-CRTC1 and Aβ₄₂ oligomers can not cause further impairment of L-LTP;CRTC1 overexpression lentivirus（LV-OE-CRTC1）can protect the L-LTP deficits induced by Aβ₄₂ oligomers.These results suggest that CRTC1 may be one of the targets of Aβ-induced L-LTP deficits in hippocampus.In our study,we further explore the downstream molecular mechanism underlying CRTC1 involved in synaptic plasticity impairment and cognitive decline in the onset of AD.Methods: C terminal amyloid precursor protein（APP）levels of hippocampus and cortex of 12-month-old APP/PS1 mice were detected by Western blotting（WB）.CRTC1 and CRE target genes levels of hippocampus and cortex of 12-month-old APP/PS1 mice were detected by WB.The CRTC1 expression in the dentate gyrus（DG）region of hippocampus was detected by immunofluorescence technique in APP/PS1 mice;The effects of stereotactic injection of Aβ₄₂ oligomers and LV-Sh-CRTC1 on the learning and memory function of rats were measured by behavioral experiments.The expression of CRTC1,CREB and CRE target genes in the rat hippocampus were detected by WB after behavioral experiment.Aβ induced L-LTP deficits in DG region were detected by using field potential recording technique to confirm whether it is mediated by CRTC1-BDNF pathway.Results: 1)The expression of APP in hippocampus and cortex of 12-month-old APP/PS1 mice significantly increased,which indicated that the transgenic mouse model was successfully constructed;2)The expression of CRTC1,BDNF and c-Fos decreased,the expression of pCRTC1 increased in the hippocampus and cortex of 12-month-old APP/PS1 mice;3)The expression of CRTC1 in the DG region of 12-month-old APP/PS1 mice is lower;4)Aβ₄₂ oligomers and LV-ShCRTC1 treatment groups showed cognitive impairment in the novel object recognition experiment and morris water maze experiment;5)Exogenous incubation with BDNF could block the L-LTP deficits induced by Aβ₄₂ oligomers and LV-Sh-CRTC1 in the hippocampal DG region individually;6)Exogenous incubation with BDNF could block the L-LTP deficits induced by the co-application of Aβ₄₂ oligomers and LV-Sh-CRTC1 in hippocampal DG region;7)The protective effect of preoverexpression of CRTC1 on the Aβ-induced L-LTP deficits can be abolished by the BDNF inhibitor,TrkB-FC and K252a.Conclusion:The expression of CRTC1 and BDNF in hippocampus and cortex decreased in the onset of AD.The CRTC1-BDNF pathway may mediate the synaptic plasticity deficits and cognitive impairment by Aβ₄₂ oligomers.