Institut de Neurociències, Departament Bioquímica i Biologia Molecular, Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain.
Rev Neurosci. 2011;22(2):153-69. doi: 10.1515/RNS.2011.018.
Gene expression changes in the brain affect cognition during normal and pathological aging. Progress in understanding the cellular processes regulating gene expression networks in cognition is relevant to develop therapeutic interventions for age-related cognitive disorders. Synaptic efficacy mediating memory storage requires the activation of specific gene expression programs regulated, among others, by the transcription factor cAMP-response element binding protein (CREB). CREB signaling is essential for long-lasting changes in synaptic plasticity that mediates the conversion of short-term memory to long-term memory. CREB signaling has been recently involved in several brain pathological conditions including cognitive and neurodegenerative disorders. The β-amyloid (Aβ) peptide, which plays a crucial role in the pathogenesis of Alzheimer's disease, alters hippocampal-dependent synaptic plasticity and memory and mediates synapse loss through the CREB signaling pathway. The fact that altered CREB signaling has been implicated in other cognitive disorders including Huntington's disease and Rubinstein-Taybi and Coffin-Lowry syndromes suggests a crucial role of CREB signaling in cognitive dysfunction. In this review paper, we summarize recent findings indicating a role of CREB and its coactivators CREB binding protein and CREB-regulated transcription coactivator in cognition during normal and pathological aging. We also discuss the development of novel therapeutic strategies based on CREB targeting to ameliorate cognitive decline in aging and cognitive disorders.
大脑中的基因表达变化会影响正常和病理性衰老过程中的认知。了解调节认知相关基因表达网络的细胞过程的进展对于开发与年龄相关的认知障碍的治疗干预措施具有重要意义。介导记忆存储的突触效能需要激活特定的基因表达程序，其中包括转录因子 cAMP 反应元件结合蛋白 (CREB)。CREB 信号对于介导短期记忆转化为长期记忆的突触可塑性的持久变化至关重要。CREB 信号已被涉及到几种脑病理状况，包括认知和神经退行性疾病。β-淀粉样蛋白 (Aβ) 肽在阿尔茨海默病的发病机制中起着关键作用，它通过 CREB 信号通路改变海马依赖性突触可塑性和记忆，并介导突触丢失。事实上，改变的 CREB 信号已被牵连到其他认知障碍，包括亨廷顿病、鲁宾斯坦-泰比和科芬-劳里综合征，这表明 CREB 信号在认知功能障碍中起着至关重要的作用。在这篇综述论文中，我们总结了最近的发现，表明 CREB 及其共激活因子 CREB 结合蛋白和 CREB 调节转录共激活因子在正常和病理性衰老过程中的认知中的作用。我们还讨论了基于 CREB 靶向的新型治疗策略的发展，以改善衰老和认知障碍中的认知衰退。
