CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease
CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease
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DOI：
10.1073/pnas.1012851108
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发表时间：
2010-12-28
影响因子：
11.1
通讯作者：
Oddo, Salvatore
中科院分区：
文献类型：
--
作者：
Caccamo, Antonella;Maldonado, Monica A.;Oddo, Salvatore
认知功能障碍和记忆丧失是阿尔茨海默病（AD）的常见特征。在AD患者的大脑中，已经报道了在记忆形成中起关键作用的立即早期基因（例如cAMP反应元件结合蛋白（CREB））的表达谱的异常。在这里，我们表明，淀粉样蛋白β（A β）的积累，这在AD的认知缺陷中起着主要作用，干扰CREB活性。我们进一步表明，通过脑病毒递送CREB结合蛋白（CBP）恢复CREB功能，可改善AD动物模型的学习和记忆缺陷。值得注意的是，这种改善在A β和tau病理学没有变化的情况下发生，而是与脑源性神经营养因子水平的增加有关。由此产生的数据表明，A β诱导的学习和记忆缺陷是由CREB功能的改变介导的，这是基于以下发现：通过直接调节成年小鼠大脑中的CBP水平来恢复CREB活性足以改善学习和记忆。因此，增加成年人大脑中CBP的表达可能不仅是AD的有效治疗方法，而且也是以立即早期基因改变为特征的各种脑部疾病的有效治疗方法，进一步支持病毒载体递送可能是神经退行性疾病的可行治疗方法的概念。神经科学
Cognitive dysfunction and memory loss are common features of Alzheimer's disease (AD). Abnormalities in the expression profile of immediate early genes that play a critical role in memory formation, such as the cAMP-response element binding protein (CREB), have been reported in the brains of AD patients. Here we show that amyloid-beta (A beta) accumulation, which plays a primary role in the cognitive deficits of AD, interferes with CREB activity. We further show that restoring CREB function via brain viral delivery of the CREB-binding protein (CBP) improves learning and memory deficits in an animal model of AD. Notably, such improvements occur without changes in A beta and tau pathology, and instead are linked to an increased level of brain-derived neurotrophic factor. The resulting data suggest that A beta-induced learning and memory deficits are mediated by alterations in CREB function, based on the finding that restoring CREB activity by directly modulating CBP levels in the brains of adult mice is sufficient to ameliorate learning and memory. Therefore, increasing CBP expression in adult brains may be a valid therapeutic approach not only for AD, but also for various brain disorders characterized by alterations in immediate early genes, further supporting the concept that viral vector delivery may be a viable therapeutic approach in neurodegenerative diseases. NEUROSCIENCE