Transcriptional regulation of N-acetylaspartate metabolism in the 5xFAD model of Alzheimer's disease: evidence for neuron-glia communication during energetic crisis.
Transcriptional regulation of N-acetylaspartate metabolism in the 5xFAD model of Alzheimer's disease: evidence for neuron-glia communication during energetic crisis.
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在阿尔茨海默氏病的5xFAD模型中，N-乙酰天冬氨酸代谢的转录调节：在能量危机期间神经元 - 胶体通信的证据。
DOI：
10.1016/j.mcn.2015.03.009
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发表时间：
2015-03
期刊：
影响因子：
--
通讯作者：
Francis JS
中科院分区：
文献类型：
--
作者：
Zaroff S;Leone P;Markov V;Francis JS
n-乙酰天冬氨酸（NAA）在整个神经退行性谱系中提供了神经元代谢完整性的非侵入性临床指标。虽然NAA的功能还没有得到全面的定义，但大脑中NAA的减少与线粒体代谢受损有关，并与ATP密切相关。我们对家族性阿尔茨海默病5xFAD小鼠模型的早期病理过程中NAA异常进行了分析，结果表明，在该模型系统中，编码限速NAA合成酶（Nat8L）的基因表达失调与线粒体氧化磷酸化缺陷有关。在5xFAD海马中，Nat8L的下调尤为明显，在此之前，少突胶质天冬氨酸酰化酶（aspa）显著上调，该酶编码大脑中唯一已知的naa分解代谢酶。5xFAD NAA和Nat8L的减少不能用神经元含量或提供苹果酸-天冬氨酸穿梭的底物活性的差异来解释，因此暗示了对病理性能量危机的协调反应中的转录调节。一项平行发育分析支持了ASPA在这种反应中的核心作用，该分析显示，在ASPA缺失的小鼠模型中，在出生后早期发育期间，Nat8L的表达高度显著增加，通常被ASPA的转录上调打断。这些结果为阿尔茨海默病的信号机制提供了初步证据，该机制涉及神经元和少突胶质细胞之间的串扰，并提示ASPA负性调节Nat8L的表达。这一机制被认为是大脑在能量危机期间保存可用底物的基本手段。
N-acetylaspartate (NAA) provides a non-invasive clinical index of neuronal metabolic integrity across the entire neurodegenerative spectrum. While NAA function is not comprehensively defined, reductions in the brain are associated with compromised mitochondrial metabolism and are tightly linked to ATP. We have undertaken an analysis of abnormalities in NAA during early stage pathology in the 5xFAD mouse model of familial Alzheimer's disease and show here that dysregulated expression of the gene encoding for the rate-limiting NAA synthetic enzyme (Nat8L) is associated with deficits in mitochondrial oxidative phosphorylation in this model system. Downreguation of Nat8L is particularly pronounced in the 5xFAD hippocampus, and is preceded by a significant upregulation of oligodendrocytic aspartoacylase (aspa), which encodes for the sole known NAA-catabolising enzyme in the brain. Reductions in 5xFAD NAA and Nat8L cannot be accounted for by discrepancies in either neuron content or activity of the substrate-providing malate-aspartate shuttle, thereby implicating transcriptional regulation in a coordinated response to pathological energetic crisis. A central role for ASPA in this response is supported by a parallel developmental analysis showing highly significant increases in Nat8L expression in an ASPA-null mouse model during a period of early postnatal development normally punctuated by the transcriptional upregulation of aspa. These results provide preliminary evidence of a signaling mechanism in Alzheimer's disease that involves cross talk between neurons and oligodendrocytes, and suggest ASPA acts to negatively regulate Nat8L expression. This mechanism is proposed to be a fundamental means by which the brain conserves available substrate during energy crises.
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DOI：
10.1093/brain/awp087
发表时间：
2009-06
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Kolodziejczyk K;Hamilton NB;Wade A;Káradóttir R;Attwell D
通讯作者：
Attwell D
影响因子：
30.8
作者：
KAUL, R;GAO, GP;MATALON, R
通讯作者：
MATALON, R
影响因子：
4.2
作者：
Signoretti, S;Marmarou, A;Vagnozzi, R
通讯作者：
Vagnozzi, R
影响因子：
4.3
作者：
Karaman, Sule;Barnett, John, Jr.;Delaney, Bryan
通讯作者：
Delaney, Bryan
影响因子：
4.1
作者：
Wiame, Elsa;Tyteca, Donatienne;Van Schaftingen, Emile
通讯作者：
Van Schaftingen, Emile