Inhibition of soluble TNF signaling in a mouse model of Alzheimer's disease prevents pre-plaque amyloid-associated neuropathology.
Inhibition of soluble TNF signaling in a mouse model of Alzheimer's disease prevents pre-plaque amyloid-associated neuropathology.
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DOI：
10.1016/j.nbd.2009.01.006
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发表时间：
2009-04
影响因子：
6.1
通讯作者：
Tansey MG
中科院分区：
文献类型：
--
作者：
McAlpine FE;Lee JK;Harms AS;Ruhn KA;Blurton-Jones M;Hong J;Das P;Golde TE;LaFerla FM;Oddo S;Blesch A;Tansey MG
阿尔茨海默病（AD）与中枢神经系统（CNS）中小胶质细胞的激活和炎症介质的过度产生有关。据报道，AD患者的血清和死后脑中促炎细胞因子肿瘤坏死因子（TNF）水平升高，但其在AD进展中的作用尚不清楚。使用新型工程化显性负性TNF抑制剂（DN-TNF）对可溶性TNF（solTNF）具有选择性，我们研究了通过长期输注重组DN-TNF XENP345或单次注射编码DN-TNF的慢病毒来阻断TNF信号传导是否可以预防3xTgAD小鼠中由慢性全身性炎症诱导的AD样病理的加速。我们发现，慢性抑制solTNF信号与任何一种方法减少了LPS诱导的积累6E10免疫反应蛋白在海马，皮质，杏仁核。使用C-末端APP抗体的免疫组织学和生物化学方法表明，积聚蛋白的主要部分可能是C-末端APP片段（β-CTF），而次要部分由A β 40和42组成。在3xTgAD小鼠中TNFR1介导的TNF信号转导的遗传失活产生了类似的结果。总之，我们的研究表明，可溶性TNF是神经炎症对3xTgAD小鼠早期（斑块前）病理学影响的关键介质。靶向抑制CNS中的solTNF可减缓AD中淀粉样蛋白相关病理、认知缺陷和潜在神经元进行性损失的出现。
Microglial activation and overproduction of inflammatory mediators in the central nervous system (CNS) have been implicated in Alzheimer's disease (AD). Elevated levels of the pro-inflammatory cytokine Tumor Necrosis Factor (TNF) have been reported in serum and post-mortem brains of patients with AD, but its role in progression of AD is unclear. Using novel engineered dominant negative TNF inhibitors (DN-TNFs) selective for soluble TNF (solTNF), we investigated whether blocking TNF signaling with chronic infusion of the recombinant DN-TNF XENP345 or a single injection of a lentivirus encoding DN-TNF prevented the acceleration of AD-like pathology induced by chronic systemic inflammation in 3xTgAD mice. We found that chronic inhibition of solTNF signaling with either approach decreased the LPS-induced accumulation of 6E10-immunoreactive protein in hippocampus, cortex, and amygdala. Immunohistological and biochemical approaches using a C-terminal APP antibody indicated that a major fraction of the accumulated protein was likely to be C-terminal APP fragments (β-CTF) while a minor fraction consisted of Aβ 40 and 42. Genetic inactivation of TNFR1-mediated TNF signaling in 3xTgAD mice yielded similar results. Taken together, our studies indicate that soluble TNF is a critical mediator of the effects of neuroinflammation on early (pre-plaque) pathology in 3xTgAD mice. Targeted inhibition of solTNF in the CNS may slow the appearance of amyloid-associated pathology, cognitive deficits, and potentially the progressive loss of neurons in AD.
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影响因子：
15.9
作者：
Fraser, SP;Suh, YH;Djamgoz, MBA
通讯作者：
Djamgoz, MBA
影响因子：
2.8
作者：
FLICK, DA;GIFFORD, GE
通讯作者：
GIFFORD, GE
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
影响因子：
2.5
作者：
FILLIT, H;DING, W;WOLFKLEIN, G
通讯作者：
WOLFKLEIN, G
影响因子：
11.2
作者：
Balosso, S;Ravizza, T;Vezzani, A
通讯作者：
Vezzani, A