Brain gene expression patterns differentiate mild cognitive impairment from normal aged and Alzheimer's disease.
Brain gene expression patterns differentiate mild cognitive impairment from normal aged and Alzheimer's disease.
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DOI：
10.1016/j.neurobiolaging.2014.03.031
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发表时间：
2014-09
影响因子：
4.2
通讯作者：
Cotman CW
中科院分区：
文献类型：
--
作者：
Berchtold NC;Sabbagh MN;Beach TG;Kim RC;Cribbs DH;Cotman CW
轻度认知障碍（MCI）代表介于正常衰老和早期阿尔茨海默病（AD）之间的认知状态。为了研究 MCI 的分子特征是否与临床情况相符，我们使用认知正常老年对照、MCI 和 AD 病例的死后组织，使用微阵列广泛分析 4 个皮质大脑区域（内嗅皮层、海马、额上回、中央后回）的基因表达。我们的数据表明，MCI 中的基因表达模式并不是衰老的延伸，并且在大多数情况下，并不介于老年对照和 AD 之间。对重要基因的功能富集分析显示，MCI 大脑中与合成代谢和生物合成途径（特别是转录、蛋白质生物合成、蛋白质运输和周转）以及线粒体能量产生相关的基因显着上调。此外，许多突触基因在 MCI 中表现出表达改变，主要是上调，包括突触囊泡融合机制、突触囊泡运输、神经递质受体以及突触结构和稳定的中心组件的基因。这些数据表明 MCI 大脑中存在突触传递的重新平衡。为了研究 MCI 中的突触基因表达水平是否与认知功能相关，计算了 MCI 病例的 MMSE 和区域特异性 mRNA 表达之间的 Pearson 相关系数。许多突触基因表现出强烈的显着相关性（r>0.8，p<0.01），在 EC 中最为显着，在 HC 中较少，在新皮质区域中也很少。具有高度显着相关性的突触基因主要与突触传递和可塑性以及髓磷脂组成有关。出乎意料的是，我们发现促进突触兴奋性和可塑性的基因表达变化绝大多数与较差的 MMSE 相关，相反，抑制可塑性的基因表达变化与 MMSE 正相关。这些数据表明，MCI 患者的边缘脑区域存在过度兴奋性和明显的可塑性，这与突触和认知功能受损有关。如果不加以控制，预计这种变化将导致兴奋性增加，进而导致代谢需求增加，最终导致进行性退化和AD。
Mild cognitive impairment (MCI) represents a cognitive state intermediate between normal aging and early Alzheimer Disease (AD). To investigate if the molecular signature of MCI parallels the clinical picture, we use microarrays to extensively profile gene expression in 4 cortical brain regions (entorhinal cortex, hippocampus, superior frontal gyrus, post-central gyrus) using post-mortem tissue from cognitively normal aged controls, MCI, and AD cases. Our data reveal that gene expression patterns in MCI are not an extension of aging, and for the most part, are not intermediate between aged controls and AD. Functional enrichment analysis of significant genes revealed prominent upregulation in MCI brains of genes associated with anabolic and biosynthetic pathways (notably transcription, protein biosynthesis, protein trafficking and turnover) as well as mitochondrial energy generation. In addition, many synaptic genes showed altered expression in MCI, predominantly upregulation, including genes for central components of the vesicle fusion machinery at the synapse, synaptic vesicle trafficking, neurotransmitter receptors, and synaptic structure and stabilization. These data suggest that there is a rebalancing of synaptic transmission in the MCI brain. To investigate if synaptic gene expression levels in MCI were related to cognitive function, Pearson’s correlation coefficient between MMSE and region-specific mRNA expression were computed for MCI cases. A number of synaptic genes showed strong significant correlations (r>0.8, p<0.01) most notably in the EC, with fewer in the HC, and very few in neocortical regions. The synaptic genes with highly significant correlations were predominantly related to synaptic transmission and plasticity, and myelin composition. Unexpectedly, we found that gene expression changes that facilitate synaptic excitability and plasticity were overwhelmingly associated with poorer MMSE, and conversely that gene expression changes that inhibit plasticity were positively associated with MMSE. These data suggest that there is excessive excitability and apparent plasticity in limbic brain regions in MCI, that is associated with impaired synaptic and cognitive function. Such changes would be predicted to contribute to increased excitability, in turn leading to greater metabolic demand and ultimately progressive degeneration and AD, if not controlled.
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影响因子：
9.3
作者：
Cribbs DH;Berchtold NC;Perreau V;Coleman PD;Rogers J;Tenner AJ;Cotman CW
通讯作者：
Cotman CW
基础大脑代谢可能会调节Abeta在轻度认知障碍中的认知作用：大脑储备的一个例子。
DOI：
10.1523/jneurosci.3669-09.2009
发表时间：
2009-11-25
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Cohen AD;Price JC;Weissfeld LA;James J;Rosario BL;Bi W;Nebes RD;Saxton JA;Snitz BE;Aizenstein HA;Wolk DA;Dekosky ST;Mathis CA;Klunk WE
通讯作者：
Klunk WE
影响因子：
16.2
作者：
Bakker A;Krauss GL;Albert MS;Speck CL;Jones LR;Stark CE;Yassa MA;Bassett SS;Shelton AL;Gallagher M
通讯作者：
Gallagher M
影响因子：
2.5
作者：
Bell, KFS;de Kort, GJL;Cuello, AC
通讯作者：
Cuello, AC
影响因子：
5.3
作者：
Akbik, Feras;Cafferty, William B. J.;Strittmatter, Stephen M.
通讯作者：
Strittmatter, Stephen M.