Institut de Neurociències, Departament Bioquímica i Biologia Molecular, Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas, Universitat Autònoma de Barcelona, Bellaterra, Spain.
Neurodegener Dis. 2012;10(1-4):250-2. doi: 10.1159/000333341. Epub 2012 Jan 6.
BACKGROUND/AIMS: Long-term memory requires fine-tuning regulation of gene expression in specific neural circuits of the brain. Transcriptional regulation of gene programs is a key mechanism for memory storage and its deregulation may contribute to synaptic and cognitive dysfunction in memory disorders. The molecular mechanisms underlying changes on activity-dependent gene expression in Alzheimer's disease (AD) are largely unknown.
We analyzed the expression of activity-dependent genes regulated by the cAMP response element binding protein (CREB) and activation of CREB and its coactivator CREB-regulated transcription coactivator 1 (CRTC1) in control and mutant β-amyloid precursor protein (APP(Sw,Ind); Swedish and Indiana mutations) transgenic mice.
Gene expression analyses revealed specific downregulation of a subset of well-known activity-induced CREB-dependent genes, including c-fos, Bdnf and Nr4a2, in the hippocampus of memory-impaired APP(Sw,Ind) transgenic mice. Activity-dependent CREB transcription induced by calcium/cAMP signals is disrupted through a mechanism involving deregulation of calcium/calcineurin-mediated dephosphorylation and activation of CRTC1. Expression of CRTC1 and pharmacological activation of L-type voltage-gated calcium channels reverse the deficits in CRTC1-mediated transcription in APP(Sw,Ind) neurons.
Our results suggest that CRTC1 dysfunction caused by Aβ accumulation underlies changes in gene expression required for hippocampal-dependent memory in AD transgenic mice.
背景/目的：长期记忆需要精细调节大脑特定神经回路中的基因表达。基因程序的转录调控是记忆存储的关键机制，其失调可能导致记忆障碍中的突触和认知功能障碍。阿尔茨海默病（AD）中活性依赖性基因表达变化的分子机制在很大程度上尚不清楚。
我们分析了受 cAMP 反应元件结合蛋白（CREB）调节的活性依赖性基因和 CREB 及其共激活因子 CREB 调节转录共激活因子 1（CRTC1）的表达在对照和突变β-淀粉样前体蛋白（APP（Sw，Ind）；瑞典和印第安纳突变）转基因小鼠。
基因表达分析显示，在记忆受损的 APP（Sw，Ind）转基因小鼠的海马体中，一组已知的活性诱导 CREB 依赖性基因的子集特异性下调，包括 c-fos、Bdnf 和 Nr4a2。通过涉及钙/钙调神经磷酸酶介导的去磷酸化和 CRTC1 激活的调节障碍，钙/CAMP 信号诱导的活性依赖性 CREB 转录受到破坏。CRTC1 的表达和 L 型电压门控钙通道的药理学激活可逆转 APP（Sw，Ind）神经元中 CRTC1 介导的转录缺陷。
我们的研究结果表明，Aβ 积累引起的 CRTC1 功能障碍是 AD 转基因小鼠海马依赖性记忆所需基因表达变化的基础。
