Neuroinflammation and Aβ accumulation linked to systemic inflammation are decreased by genetic PKR down-regulation.
Neuroinflammation and Aβ accumulation linked to systemic inflammation are decreased by genetic PKR down-regulation.
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DOI：
10.1038/srep08489
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发表时间：
2015-02-17
影响因子：
4.6
通讯作者：
Hugon J
中科院分区：
文献类型：
--
作者：
Carret-Rebillat AS;Pace C;Gourmaud S;Ravasi L;Montagne-Stora S;Longueville S;Tible M;Sudol E;Chang RC;Paquet C;Mouton-Liger F;Hugon J
阿尔茨海默病 (AD) 是一种神经退行性疾病，其特征是由淀粉样蛋白 - β (Aβ) 肽组成的老年斑、神经原纤维缠结、神经元丢失和神经炎症。先前的研究表明，全身炎症可能导致神经炎症并增强 Aβ 脑浓度。导致这些事件的分子途径尚未完全了解。 PKR 是一种促凋亡激酶，可引发炎症并在 AD 患者的大脑和脑脊液中积聚。本研究的目的是评估 LPS 诱导的神经炎症和 Aβ 的产生是否可以通过基因 PKR 下调来改变。结果表明，在注射LPS的野生型小鼠的海马中，神经炎症、细胞因子释放和Aβ产生显着增加，而在LPS处理的PKR敲除小鼠中则没有。此外，在 PKR 敲除小鼠的大脑中，BACE1 和激活的 STAT3（一种假定的 BACE1 转录调节因子）的水平并未像在野生型小鼠中观察到的那样增加。使用 PET 成像，在 LPS 处理的 PKR 敲除小鼠中没有观察到由全身 LPS 引起的海马代谢减少。总而言之，这些发现表明 PKR 在 LPS 诱导的大脑变化中发挥着重要作用，并且可能是调节神经炎症和 Aβ 产生的有效靶点。
Alzheimer's disease (AD) is a neurodegenerative disorder, marked by senile plaques composed of amyloid-β (Aβ) peptide, neurofibrillary tangles, neuronal loss and neuroinflammation. Previous works have suggested that systemic inflammation could contribute to neuroinflammation and enhanced Aβ cerebral concentrations. The molecular pathways leading to these events are not fully understood. PKR is a pro-apoptotic kinase that can trigger inflammation and accumulates in the brain and cerebrospinal fluid of AD patients. The goal of the present study was to assess if LPS-induced neuroinflammation and Aβ production could be altered by genetic PKR down regulation. The results show that, in the hippocampus of LPS-injected wild type mice, neuroinflammation, cytokine release and Aβ production are significantly increased and not in LPS-treated PKR knock-out mice. In addition BACE1 and activated STAT3 levels, a putative transcriptional regulator of BACE1, were not found increased in the brain of PKR knock-out mice as observed in wild type mice. Using PET imaging, the decrease of hippocampal metabolism induced by systemic LPS was not observed in LPS-treated PKR knock-out mice. Altogether, these findings demonstrate that PKR plays a major role in brain changes induced by LPS and could be a valid target to modulate neuroinflammation and Aβ production.
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影响因子：
3.7
作者：
Dumurgier J;Mouton-Liger F;Lapalus P;Prevot M;Laplanche JL;Hugon J;Paquet C;Groupe d’Investigation du Liquide Cephalorachidien (GIL) Study Network
通讯作者：
Groupe d’Investigation du Liquide Cephalorachidien (GIL) Study Network
影响因子：
9.3
作者：
Krstic D;Madhusudan A;Doehner J;Vogel P;Notter T;Imhof C;Manalastas A;Hilfiker M;Pfister S;Schwerdel C;Riether C;Meyer U;Knuesel I
通讯作者：
Knuesel I
影响因子：
2.7
作者：
Kahn, Marielle S.;Kranjac, Dinko;Chumley, Michael J.
通讯作者：
Chumley, Michael J.
影响因子：
5.3
作者：
Kitazawa, M;Oddo, S;LaFerla, FM
通讯作者：
LaFerla, FM
影响因子：
4.8
作者：
Bonnet, Marion C.;Daurat, Caroline;Meurs, Eliane F.
通讯作者：
Meurs, Eliane F.