Institut de Neurociències, Department de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona 08193, Spain, and Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED) and Institut de Neuropatologia, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, Barcelona 08907, Spain.
J Neurosci. 2014 Apr 23;34(17):5776-87. doi: 10.1523/JNEUROSCI.5288-13.2014.
Cognitive decline is associated with gene expression changes in the brain, but the transcriptional mechanisms underlying memory impairments in cognitive disorders, such as Alzheimer's disease (AD), are largely unknown. Here, we aimed to elucidate relevant mechanisms responsible for transcriptional changes underlying early memory loss in AD by examining pathological, behavioral, and transcriptomic changes in control and mutant β-amyloid precursor protein (APPSw,Ind) transgenic mice during aging. Genome-wide transcriptome analysis using mouse microarrays revealed deregulation of a gene network related with neurotransmission, synaptic plasticity, and learning/memory in the hippocampus of APPSw,Ind mice after spatial memory training. Specifically, APPSw,Ind mice show changes on a cAMP-responsive element binding protein (CREB)-regulated transcriptional program dependent on the CREB-regulated transcription coactivator-1 (Crtc1). Interestingly, synaptic activity and spatial memory induces Crtc1 dephosphorylation (Ser151), nuclear translocation, and Crtc1-dependent transcription in the hippocampus, and these events are impaired in APPSw,Ind mice at early pathological and cognitive decline stages. CRTC1-dependent genes and CRTC1 levels are reduced in human hippocampus at intermediate Braak III/IV pathological stages. Importantly, adeno-associated viral-mediated Crtc1 overexpression in the hippocampus efficiently reverses Aβ-induced spatial learning and memory deficits by restoring a specific subset of Crtc1 target genes. Our results reveal a critical role of Crtc1-dependent transcription on spatial memory formation and provide the first evidence that targeting brain transcriptome reverses memory loss in AD.
认知能力下降与大脑中的基因表达变化有关，但认知障碍（如阿尔茨海默病）中记忆损伤的转录机制在很大程度上尚不清楚。在这里，我们旨在通过检查对照和突变β-淀粉样前体蛋白（APPSw，Ind）转基因小鼠在衰老过程中的病理、行为和转录组变化，阐明导致 AD 早期记忆丧失的相关转录变化的机制。使用小鼠微阵列进行全基因组转录组分析显示，在空间记忆训练后，APPSw，Ind 小鼠的海马体中与神经传递、突触可塑性和学习/记忆相关的基因网络发生了失调。具体而言，APPSw，Ind 小鼠表现出 cAMP 反应元件结合蛋白（CREB）调节的转录程序的变化，该程序依赖于 CREB 调节的转录共激活因子-1（Crtc1）。有趣的是，突触活动和空间记忆会诱导 Crtc1 去磷酸化（Ser151）、核转位以及海马体中的 Crtc1 依赖性转录，而在早期病理和认知衰退阶段，APPSw，Ind 小鼠的这些事件受损。在中间 Braak III/IV 病理阶段，人类海马体中的 CRTC1 依赖性基因和 CRTC1 水平降低。重要的是，腺相关病毒介导的 Crtc1 在海马体中的过表达通过恢复特定的 Crtc1 靶基因子集有效地逆转了 Aβ 诱导的空间学习和记忆缺陷。我们的研究结果揭示了 Crtc1 依赖性转录在空间记忆形成中的关键作用，并提供了第一个证据，表明靶向大脑转录组可以逆转 AD 中的记忆丧失。
