CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy
CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy
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DOI：
10.1093/hmg/ddr492
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发表时间：
2012-01-15
影响因子：
3.5
通讯作者：
Lu, Hui-Chen
中科院分区：
文献类型：
--
作者：
Ljungberg, M. Cecilia;Ali, Yousuf O.;Lu, Hui-Chen
以磷酸化tau蛋白的神经原纤维缠结(NFT)为特征的tau病是一组神经退行性疾病，包括额颞部痴呆和散发性和家族性阿尔茨海默病。人类tau(P301L)是一种与17号染色体连锁的额颞性痴呆相关的突变，在rTg4510小鼠中前脑特异的过度表达会导致NFTs的形成、学习和记忆障碍以及大量神经元死亡。在这里，我们表明，在rTg4510小鼠中，NMNA2(烟酰胺单核苷酸腺苷转移酶2)的mRNA和蛋白水平在神经变性或认知缺陷开始之前就降低了。NMNA2是一种最近被发现的维持周围神经神经元健康的生存因子。在nmnat2启动子区域发现了两个功能性cAMP反应元件(Cres)。RTg4510小鼠大脑皮层和海马区磷酸化Cre结合蛋白(CREB)总量和结合nmnat2 Cre位点的pCREB均显著减少，提示NMNA2是CREB在生理条件下的直接靶标，tau(P301L)过表达下调了CREB介导的转录。我们发现，使用重组腺相关病毒载体在6周龄的rTg4510海马区过度表达NMNA2或其同系物NMNA1，而不是NMNA3，显著减少了5月龄tau(P301L)过表达引起的神经变性。综上所述，我们的研究有力地支持了NMNA2在哺乳动物中枢神经系统中的保护作用。病理性损伤时CREB信号的减少导致内源性NMNA2功能下降可能是神经细胞死亡的潜在机制之一。
Tauopathies, characterized by neurofibrillary tangles (NFTs) of phosphorylated tau proteins, are a group of neurodegenerative diseases, including frontotemporal dementia and both sporadic and familial Alzheimer's disease. Forebrain-specific over-expression of human tau(P301L), a mutation associated with frontotemporal dementia with parkinsonism linked to chromosome 17, in rTg4510 mice results in the formation of NFTs, learning and memory impairment and massive neuronal death. Here, we show that the mRNA and protein levels of NMNAT2 (nicotinamide mononucleotide adenylyltransferase 2), a recently identified survival factor for maintaining neuronal health in peripheral nerves, are reduced in rTg4510 mice prior to the onset of neurodegeneration or cognitive deficits. Two functional cAMP-response elements (CREs) were identified in the nmnat2 promoter region. Both the total amount of phospho-CRE binding protein (CREB) and the pCREB bound to nmnat2 CRE sites in the cortex and the hippocampus of rTg4510 mice are significantly reduced, suggesting that NMNAT2 is a direct target of CREB under physiological conditions and that tau(P301L) overexpression down-regulates CREB-mediated transcription. We found that over-expressing NMNAT2 or its homolog NMNAT1, but not NMNAT3, in rTg4510 hippocampi from 6 weeks of age using recombinant adeno-associated viral vectors significantly reduced neurodegeneration caused by tau(P301L) over-expression at 5 months of age. In summary, our studies strongly support a protective role of NMNAT2 in the mammalian central nervous system. Decreased endogenous NMNAT2 function caused by reduced CREB signaling during pathological insults may be one of underlying mechanisms for neuronal death in tauopathies.