CCL2 accelerates microglia-mediated Abeta oligomer formation and progression of neurocognitive dysfunction.
CCL2 accelerates microglia-mediated Abeta oligomer formation and progression of neurocognitive dysfunction.
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DOI：
10.1371/journal.pone.0006197
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发表时间：
2009-07-10
期刊：
影响因子：
3.7
通讯作者：
Ikezu T
中科院分区：
文献类型：
--
作者：
Kiyota T;Yamamoto M;Xiong H;Lambert MP;Klein WL;Gendelman HE;Ransohoff RM;Ikezu T
神经炎症和阿尔茨海默病（AD）发病机制之间的联系已经很好地建立。然而，具体的免疫途径和蛋白质是如何影响疾病的。为此，我们先前证明，转基因CCL 2过度表达增强小胶质细胞增生，并诱导弥漫性淀粉样斑块沉积在Tg 2576小鼠。该AD啮齿动物模型表达瑞典β-淀粉样蛋白（Aβ）前体蛋白突变体。我们现在报道，早在2-3个月大的β-淀粉样前体蛋白（APP）小鼠中，CCL 2转基因表达加速了空间和工作记忆以及海马突触传递的缺陷。随后在Aβ寡聚体周围观察到的小胶质细胞数量增加。CCL 2不抑制Aβ降解。相反，CCL 2和肿瘤坏死因子-α直接促进Aβ摄取、细胞内Aβ寡聚化和蛋白分泌。我们证实CCL 2促进小胶质细胞中Aβ寡聚体的形成，并提出此类事件通过影响大脑中的Aβ播种而加速记忆功能障碍。
The linkages between neuroinflammation and Alzheimer's disease (AD) pathogenesis are well established. What is not, however, is how specific immune pathways and proteins affect the disease. To this end, we previously demonstrated that transgenic over-expression of CCL2 enhanced microgliosis and induced diffuse amyloid plaque deposition in Tg2576 mice. This rodent model of AD expresses a Swedish β-amyloid (Aβ) precursor protein mutant. We now report that CCL2 transgene expression accelerates deficits in spatial and working memory and hippocampal synaptic transmission in β-amyloid precursor protein (APP) mice as early as 2–3 months of age. This is followed by increased numbers of microglia that are seen surrounding Aβ oligomers. CCL2 does not suppress Aβ degradation. Rather, CCL2 and tumor necrosis factor-α directly facilitated Aβ uptake, intracellular Aβ oligomerization, and protein secretion. We posit that CCL2 facilitates Aβ oligomer formation in microglia and propose that such events accelerate memory dysfunction by affecting Aβ seeding in the brain.
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影响因子：
5.3
作者：
Hickman, Suzanne E.;Allison, Elizabeth K.;El Khoury, Joseph
通讯作者：
El Khoury, Joseph
影响因子：
4.8
作者：
Moechars, D;Dewachter, I;Van Leuven, F
通讯作者：
Van Leuven, F
DOI：
10.1007/s10162-006-0051-x
发表时间：
2006-12
影响因子：
2.4
作者：
Sautter, Nathan B.;Shick, Elizabeth H.;Ransohoff, Richard M.;Charo, Israel F.;Hirose, Keiko
通讯作者：
Hirose, Keiko
影响因子：
15.8
作者：
Jankowsky JL;Slunt HH;Gonzales V;Savonenko AV;Wen JC;Jenkins NA;Copeland NG;Younkin LH;Lester HA;Younkin SG;Borchelt DR
通讯作者：
Borchelt DR
影响因子：
25
作者：
Chapman, PF;White, GL;Hsiao, KK
通讯作者：
Hsiao, KK