Microglia activation mediates fibrillar amyloid-β toxicity in the aged primate cortex.
Microglia activation mediates fibrillar amyloid-β toxicity in the aged primate cortex.
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DOI：
10.1016/j.neurobiolaging.2009.02.025
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发表时间：
2011-03
影响因子：
4.2
通讯作者：
Geula C
中科院分区：
文献类型：
--
作者：
Leung E;Guo L;Bu J;Maloof M;El Khoury J;Geula C
淀粉样蛋白-β多肽(A-β)在阿尔茨海默病(AD)的发病机制中起核心作用。纤维状的A-β(FA-β)通过尚不清楚的机制对神经元产生毒性作用。我们已经证明，老化的灵长类皮质在低浓度下选择性地容易受到FAβ毒性的影响。除神经元丢失外，FAβ还可诱导老年恒河猴皮质小胶质细胞的大量激活。我们现在证明，抑制小胶质细胞激活可以消除FAβ的毒性。注射或泵送巨噬细胞/小胶质细胞抑制因子可显著减少FAβ引起的小胶质细胞活化和损伤体积。分离的老年恒河猴皮质小胶质细胞在FA-β刺激下产生大量的活性氧，并呈剂量依赖性抑制。这是第一个明确的体内证据表明，FAβ诱导的小胶质细胞激活和炎症至少在一定程度上介导了其对神经元的毒性效应。结合我们早期的观察，这些发现表明，与年轻的小胶质细胞相比，老年灵长类动物的小胶质细胞可能对FAβ表现出夸大的炎症反应。
The amyloid-β peptide (Aβ) plays a central role in the pathogenesis of Alzheimer's disease (AD). The fibrillar form of Aβ (fAβ) exerts toxic effects on neurons through mechanisms not well understood. We have shown that the aged primate cortex is selectively vulnerable to fAβ toxicity at low concentrations. In addition to neuronal loss, fAβ induced massive activation of microglia in the aged rhesus cortex. We now demonstrate that inhibition of microglia activation abolishes fAβ toxicity. Injection or pump delivery of macrophage/microglia inhibitory factor (MIF) significantly reduced activation of microglia and the volume of damage caused by fAβ. Microglia isolated from aged rhesus cortex produced substantial reactive oxygen species when stimulated by fAβ, which was inhibited by MIF in a dose-dependent manner. This is the first definitive in vivo demonstration that the fAβ-induced microglia activation and inflammation mediate, at least in part, its toxic effects on neurons. Combined with our earlier observations, these findings suggest that aged primate microglia may display an exaggerated inflammatory response to fAβ when compared with young microglia.
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影响因子：
105.7
作者：
Etminan, M;Gill, S;Samii, A
通讯作者：
Samii, A
CD36介导了对β-淀粉样蛋白的先天宿主反应。
影响因子：
15.3
作者：
El Khoury, JB;Moore, KJ;Means, TK;Leung, J;Terada, K;Toft, M;Freeman, MW;Luster, AD
通讯作者：
Luster, AD
DOI：
10.1073/pnas.96.14.8212
发表时间：
1999-07-06
影响因子：
11.1
作者：
Kaul, M;Lipton, SA
通讯作者：
Lipton, SA
影响因子：
6
作者：
Coraci, IS;Husemann, J;El Khoury, JB
通讯作者：
El Khoury, JB
影响因子：
82.9
作者：
Geula, C;Wu, CK;Yankner, BA
通讯作者：
Yankner, BA