Hippocampal expression of murine TNFα results in attenuation of amyloid deposition in vivo.
Hippocampal expression of murine TNFα results in attenuation of amyloid deposition in vivo.
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DOI：
10.1186/1750-1326-6-16
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发表时间：
2011-02-16
影响因子：
15.1
通讯作者：
Golde TE
中科院分区：
文献类型：
--
作者：
Chakrabarty P;Herring A;Ceballos-Diaz C;Das P;Golde TE
纤维状淀粉样β（fAβ）肽是阿尔茨海默病（AD）患者大脑中Aβ斑块的主要成分。先前有人提出炎症介质通过增加APP的淀粉样生成加工过程和促进Aβ积累，是AD患者Aβ病理的驱动因素，但最近的数据表明，多种炎症细胞因子的表达可减轻小鼠模型中的Aβ病理。为了进一步研究不同炎症细胞因子在体内对Aβ病理的作用，我们探究了小鼠肿瘤坏死因子α（mTNFα）在调节Aβ积累方面的作用。重组腺相关病毒血清型1（AAV2/1）介导的mTNFα在4个月大的APP转基因TgCRND8小鼠海马中的表达，导致海马Aβ负荷显著降低。在表达mTNFα的APP转基因小鼠或非转基因同窝小鼠中，均未观察到APP水平或APP加工过程的变化。对表达mTNFα的小鼠的Aβ斑块负荷分析表明，即使与表达EGFP的年龄匹配的对照组相比有显著降低，前者的Aβ斑块负荷水平也没有降低到4个月大未处理小鼠的水平。综上所述，我们的数据表明，促炎细胞因子表达诱导的强烈胶质细胞激活可减轻斑块沉积。这种增强的小胶质细胞反应是否真的能清除已有的沉积物而不引起旁观者神经毒性，仍然是一个未解决的问题。
Fibrillar amyloid β (fAβ) peptide is the major component of Aβ plaques in the brains of Alzheimer's disease (AD) patients. Inflammatory mediators have previously been proposed to be drivers of Aβ pathology in AD patients by increasing amyloidogenic processing of APP and promoting Aβ accumulation, but recent data have shown that expression of various inflammatory cytokines attenuates Aβ pathology in mouse models. In an effort to further study the role of different inflammatory cytokines on Aβ pathology in vivo, we explored the effect of murine Tumor Necrosis Factor α (mTNFα) in regulating Aβ accumulation. Recombinant adeno-associated virus serotype 1 (AAV2/1) mediated expression of mTNFα in the hippocampus of 4 month old APP transgenic TgCRND8 mice resulted in significant reduction in hippocampal Aβ burden. No changes in APP levels or APP processing were observed in either mTNFα expressing APP transgenic mice or in non-transgenic littermates. Analysis of Aβ plaque burden in mTNFα expressing mice showed that even after substantial reduction compared to EGFP expressing age-matched controls, the Aβ plaque burden levels of the former do not decrease to the levels of 4 month old unmanipulated mice. Taken together, our data suggests that proinflammatory cytokine expression induced robust glial activation can attenuate plaque deposition. Whether such an enhanced microglial response actually clears preexisting deposits without causing bystander neurotoxicity remains an open question.
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影响因子：
5.1
作者：
Covey, WC;Ignatowski, TA;Spengler, RN
通讯作者：
Spengler, RN
影响因子：
6
作者：
Janelsins, Michelle C.;Mastrangelo, Michael A.;Bowers, William J.
通讯作者：
Bowers, William J.
影响因子：
30.8
作者：
LAMB, BT;SISODIA, SS;GEARHART, JD
通讯作者：
GEARHART, JD
小胶质细胞激活与增强的肿瘤坏死因子-Alpha和单核细胞化学吸收剂蛋白-1表达的早期相关性在三重转基因阿尔茨海默氏病小鼠的内嗅皮层中特异性。
影响因子：
9.3
作者：
Janelsins, Michelle C.;Mastrangelo, Michael A.;Oddo, Salvatore;LaFerla, Frank M.;Federoff, Howard J.;Bowers, William J.
通讯作者：
Bowers, William J.
DOI：
10.1083/jcb.200705042
发表时间：
2007-08-27
期刊：
The Journal of cell biology
影响因子：
--
作者：
He P;Zhong Z;Lindholm K;Berning L;Lee W;Lemere C;Staufenbiel M;Li R;Shen Y
通讯作者：
Shen Y