Poly(ADP-ribose)polymerase-1 modulates microglial responses to amyloid β.
Poly(ADP-ribose)polymerase-1 modulates microglial responses to amyloid β.
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DOI：
10.1186/1742-2094-8-152
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发表时间：
2011-11-03
影响因子：
9.3
通讯作者：
Swanson RA
中科院分区：
文献类型：
--
作者：
Kauppinen TM;Suh SW;Higashi Y;Berman AE;Escartin C;Won SJ;Wang C;Cho SH;Gan L;Swanson RA
β淀粉样蛋白（Aβ）在阿尔茨海默病（AD）的大脑中积累。小胶质细胞激活也发生在阿尔茨海默病中，这种炎症反应可能有助于疾病的进展。Aβ可以诱导小胶质细胞活化，但其发生的机制尚未明确。核酶聚（adp -核糖）聚合酶-1 （PARP-1）通过与转录因子NF-κB的相互作用，在多种刺激下调节小胶质细胞的激活。本研究的目的是评估PARP-1激活是否参与Aβ诱导的小胶质细胞激活，以及PARP-1抑制是否可以改变小胶质细胞对Aβ的反应。我们将随着衰老积累Aβ的hAPPJ20小鼠与PARP-1-/-小鼠杂交，以评估PARP-1缺失对小胶质细胞激活、海马突触完整性和认知功能的影响。同时在wt和PARP-1-/-小鼠脑内注射Aβ肽，直接测定PARP-1对Aβ诱导的小胶质细胞活化的影响。利用PARP-1-/-细胞和PARP-1抑制剂，在原代小胶质细胞培养和小胶质-神经元共培养中评估了PARP-1对a β诱导的小胶质细胞因子产生和神经毒性的影响。研究了慢病毒报告基因感染的小胶质细胞中NF-κB的活化情况。6个月大时，hAPPJ20小鼠出现小胶质细胞激活，海马CA1钙结合蛋白表达减少，新物体识别受损。所有这些特征在hAPPJ20/PARP-1-/-小鼠中都减弱了。同样，a - β1-42注射到小鼠大脑中，在野生型小鼠中产生了强大的小胶质细胞反应，而在缺乏PARP-1表达或活性的小鼠中，这种反应被阻断。利用小胶质细胞培养的研究表明，PARP-1活性是a β诱导的NF-κB活化、形态转化、NO释放、TNFα释放和神经毒性所必需的。相反，PARP-1抑制增加了神经营养因子TGFβ和VEGF的释放，并且不影响小胶质细胞对Aβ肽的吞噬。这些结果表明，PARP-1在a β诱导的小胶质细胞活化中是一个必要的、以前未被认识到的因素，并表明PARP-1的作用至少部分是通过其与NF-κB的相互作用介导的。PARP-1抑制对a β诱导的小胶质细胞激活和神经毒性的抑制表明，这种方法可能对阿尔茨海默病和其他可能有小胶质神经毒性的疾病有用。
Amyloid β (Aβ) accumulates in Alzheimer's disease (AD) brain. Microglial activation also occurs in AD, and this inflammatory response may contribute to disease progression. Microglial activation can be induced by Aβ, but the mechanisms by which this occurs have not been defined. The nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) regulates microglial activation in response to several stimuli through its interactions with the transcription factor, NF-κB. The purpose of this study was to evaluate whether PARP-1 activation is involved in Aβ-induced microglial activation, and whether PARP-1 inhibition can modify microglial responses to Aβ. hAPPJ20 mice, which accumulate Aβ with ageing, were crossed with PARP-1-/- mice to assess the effects of PARP-1 depletion on microglial activation, hippocampal synaptic integrity, and cognitive function. Aβ peptide was also injected into brain of wt and PARP-1-/- mice to directly determine the effects of PARP-1 on Aβ-induced microglial activation. The effect of PARP-1 on Aβ-induced microglial cytokine production and neurotoxicity was evaluated in primary microglia cultures and in microglia-neuron co-cultures, utilizing PARP-1-/- cells and a PARP-1 inhibitor. NF-κB activation was evaluated in microglia infected with a lentivirus reporter gene. The hAPPJ20 mice developed microglial activation, reduced hippocampal CA1 calbindin expression, and impaired novel object recognition by age 6 months. All of these features were attenuated in hAPPJ20/PARP-1-/- mice. Similarly, Aβ1-42 injected into mouse brain produced a robust microglial response in wild-type mice, and this was blocked in mice lacking PARP-1 expression or activity. Studies using microglial cultures showed that PARP-1 activity was required for Aβ-induced NF-κB activation, morphological transformation, NO release, TNFα release, and neurotoxicity. Conversely, PARP-1 inhibition increased release of the neurotrophic factors TGFβ and VEGF, and did not impair microglial phagocytosis of Aβ peptide. These results identify PARP-1 as a requisite and previously unrecognized factor in Aβ-induced microglial activation, and suggest that the effects of PARP-1 are mediated, at least in part, by its interactions with NF-κB. The suppression of Aβ-induced microglial activation and neurotoxicity by PARP-1 inhibition suggests this approach could be useful in AD and other disorders in which microglial neurotoxicity may contribute.
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影响因子：
4.7
作者：
Chiarugi, A;Moskowitz, MA
通讯作者：
Moskowitz, MA
影响因子：
4.8
作者：
Chang, WJ;Alvarez-Gonzalez, R
通讯作者：
Alvarez-Gonzalez, R
影响因子：
2.5
作者：
Familian, Atoosa;Eikelenboom, Piet;Veerhuis, Robert
通讯作者：
Veerhuis, Robert
影响因子：
4.8
作者：
Chen, J;Zhou, YG;Li, G
通讯作者：
Li, G
影响因子：
16
作者：
Cohen-Armon, Malka;Visochek, Leonid;Seger, Rony
通讯作者：
Seger, Rony