CA1 Nampt knockdown recapitulates hippocampal cognitive phenotypes in old mice which nicotinamide mononucleotide improves.
CA1 Nampt knockdown recapitulates hippocampal cognitive phenotypes in old mice which nicotinamide mononucleotide improves.
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DOI：
10.1038/s41514-018-0029-z
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发表时间：
2018
影响因子：
5
通讯作者：
Imai S
中科院分区：
文献类型：
--
作者：
Johnson S;Wozniak DF;Imai S
认知功能障碍是全球人口老龄化最令人关注的结果之一。然而，认知功能在衰老过程中受损的机制仍然难以捉摸。已经确定，NAD+水平在多个组织和器官中降低，包括大脑。我们发现，在衰老过程中，小鼠海马中的NAD+水平下降，而我们观察到老年小鼠的空间学习/记忆能力与年龄相关的影响最小，我们发现它们在情境恐惧条件反射测试中对厌恶刺激产生认知超敏反应。这种认知超敏反应似乎与情绪（恐惧/焦虑）和感觉处理（休克敏感性）的改变有关，而不是反映衰老过程中真正的条件反射/保留效应。补充烟酰胺单胞苷肽（NMN）改善了超敏反应的感觉加工方面，并可能改善其他相关行为。特异性敲除CA 1区的烟酰胺磷酸核糖转移酶（Nampt），但不在齿状回，概括了在老年小鼠中观察到的这种认知超敏反应。我们确定钙/钙调蛋白依赖性丝氨酸蛋白激酶（Cask）作为一个潜在的下游效应器，在海马中与年龄相关的NAD+减少。Cask表达对NAD+变化有响应，并且在衰老期间在海马中也减少。短期补充NMN可增强老龄小鼠海马中Cask的表达。其启动子活性以Sirt 1依赖性方式调节。总而言之，CA 1区域的NAD+减少会导致与年龄相关的认知功能障碍的发展，其中的某些方面可以通过补充NAD+中间体（例如NMN）来增强NAD+的可用性来预防或治疗。认知功能障碍是全球人口老龄化最令人关注的结果之一。然而，衰老过程中认知障碍的机制仍然难以捉摸。我们发现，在老年小鼠中，所有生物体必需的化学物质烟酰胺腺嘌呤二核苷酸（NAD+）的水平在海马体中下降，海马体是大脑记忆和学习的关键部分。我们还发现，认知和行为功能的年龄相关性超敏反应（认知超敏反应）是由海马中NAD+可用性降低引起的。补充烟酰胺单甘肽（NMN），一种转化为NAD+的关键化学物质，能够减轻在老年小鼠中观察到的认知超敏反应。我们的研究结果为NAD+下降如何影响与年龄相关的焦虑/抑郁以及如何通过增强NAD+来预防或治疗此类损伤提供了新的见解。
Cognitive dysfunction is one of the most concerning outcomes in global population aging. However, the mechanisms by which cognitive functions are impaired during aging remain elusive. It has been established that NAD+ levels are reduced in multiple tissues and organs, including the brain. We found that NAD+ levels declined in the hippocampus of mice during the course of aging, and whereas we observed minimal age-related effects on spatial learning/memory capabilities in old mice, we discovered that they developed cognitive hypersensitivity in response to aversive stimulation during contextual fear conditioning tests. This cognitive hypersensitivity appears to be associated with alterations in emotionality (fear/anxiety) and sensory processing (shock sensitivity), rather than reflect genuine conditioning/retention effects, during aging. Supplementation of nicotinamide mononucleotide (NMN) improved the sensory processing aspect of the hypersensitivity and possibly other related behaviors. Specific knockdown of nicotinamide phosphoribosyltransferase (Nampt) in the CA1 region, but not in the dentate gyrus, recapitulates this cognitive hypersensitivity observed in old mice. We identified calcium/calmodulin-dependent serine protein kinase (Cask) as a potential downstream effector in response to age-associated NAD+ reduction in the hippocampus. Cask expression is responsive to NAD+ changes and also reduced in the hippocampus during aging. Short-term NMN supplementation can enhance Cask expression in the hippocampus of old mice. Its promoter activity is regulated in a Sirt1-dependent manner. Taken together, NAD+ reduction in the CA1 region contributes to development of age-associated cognitive dysfunction, aspects of which may be prevented or treated by enhancing NAD+ availability through supplementation of NAD+ intermediates, such as NMN. Cognitive dysfunction is one of the most concerning outcomes in global population aging. However, the mechanisms of cognitive impairment during aging remain elusive. We found that in old mice, levels of nicotinamide adenine dinucleotide (NAD+), an essential chemical for all living organisms, declined in the hippocampus, a critical part of the brain for memory and learning. We also found that age-associated hypersensitivity in cognitive and behavioral functions (cognitive hypersensitivity) was induced by reduced NAD+ availability in the hippocampus. Supplementation of nicotinamide mononucleotide (NMN), a critical chemical that is converted to NAD+, is able to mitigate the cognitive hypersensitivity observed in old mice. Our findings provide new insights into how NAD+ decline affects age-associated anxiety/depression and how such impairments can be prevented or treated by enhancing NAD+.