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  • Title: Dysregulated CRTC1-BDNF signaling pathway in the hippocampus contributes to Aβ oligomer-induced long-term synaptic plasticity and memory impairment.
    Author: Yan P, Xue Z, Li D, Ni S, Wang C, Jin X, Zhou D, Li X, Zhao X, Chen X, Cui W, Xu D, Zhou W, Zhang J.
    Journal: Exp Neurol; 2021 Nov; 345():113812. PubMed ID: 34274327.
    Abstract:
    Expression of CREB-regulated transcription coactivator 1 (CRTC1) in the hippocampus is impaired in Alzheimer's disease (AD). However, CRTC1 related mechanisms associated with long-term synaptic plasticity impairment and cognitive decline in the onset of AD are unknown. In this study, electrophysiological recordings indicated that lentivirus-mediated CRTC1 overexpression effectively ameliorates suppression of late-phase long-term potentiation (L-LTP) in rat hippocampal slices treated with oligomeric amyloid β(1-42) peptides (oAβ42) (200 nM). In addition, application of oAβ42 and genetic knockdown of CRTC1 by lentivirus-mediated CRTC1-shRNA inhibit L-LTP, whereas their combination does not further impair L-LTP. Brain-derived neurotrophic factor (BDNF), an important downstream protein confers protection of CRTC1 overexpression against oAβ42-induced L-LTP impairment as shown by administration of K252a (200 nM) and TrkB-FC (20 μg/ml). Furthermore, behavioral and western blotting analyses showed that CRTC1 overexpression reverses oAβ42-induced hippocampal-dependent cognitive deficits, downregulation of CRTC1 and BDNF expression. Notably, CRTC1-shRNA directly elicits cognitive deficits. In summary, these findings show that hippocampal CRTC1 signaling is affected by soluble oAβ, and CRTC1-BDNF pathway is involved in hippocampal L-LTP impairment and memory deficits induced by oAβ42.
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