Dysregulated CRTC1-BDNF signaling pathway in the hippocampus contributes to Aβ oligomer-induced long-term synaptic plasticity and memory impairment

• Published in: Experimental neurology 2021-11, Vol.345, p.113812-113812, Article 113812
• Main Authors: Yan, Peiyun, Xue, Zhancheng, Li, Dezhu, Ni, Saiqi, Wang, Chuang, Jin, Xinchun, Zhou, Dongsheng, Li, Xingxing, Zhao, Xin, Chen, Xiaowei, Cui, Wei, Xu, Dingli, Zhou, Wenhua, Zhang, Junfang
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Amyloid beta-Peptides - toxicity; Animals; Aβ oligomer; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - biosynthesis; CREB-regulated transcription coactivator 1; HEK293 Cells; Hippocampus - drug effects; Hippocampus - metabolism; Humans; Late-phase long-term potentiation; Long-Term Potentiation - drug effects; Long-Term Potentiation - physiology; Male; Memory; Memory Disorders - chemically induced; Memory Disorders - metabolism; Neuronal Plasticity - drug effects; Neuronal Plasticity - physiology; Peptide Fragments - toxicity; Rats; Rats, Wistar; Signal Transduction - drug effects; Signal Transduction - physiology; Transcription Factors - biosynthesis
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2021.113812

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. •oAβ42 impaired the expression of CRTC1 and BDNF in the hippocampus of rats.•CRTC1 overexpression attenuated oAβ42-induced memory deficits in rats.•CRTC1 mediated oAβ42-induced L-LTP impairment via BDNF.