Microglia activation mediates fibrillar amyloid-β toxicity in the aged primate cortex

NEUROBIOLOGY OF AGING

卷:32

Article

Leung, Elaine^1,2,3  Guo, Ling¹  Bu, Jing^1,2,3  Maloof, Marie^1,2,3  El Khoury, Joseph^2,4  Geula, Changiz^1,2,3 

[1] Northwestern Univ, Feinberg Sch Med, Lab Cognit & Mol Morphometry, Cognit Neurol & Alzheimers Dis Ctr, Chicago, IL 60611 USA

[2] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

[3] Beth Israel Deaconess Med Ctr, Div Gerontol, Boston, MA 02215 USA

[4] Massachusetts Gen Hosp, Div Infect Dis, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA

关键词: Amyloid toxicity;    Microglia;    Fibrillar;    Neuronal loss;    Non-human primate;   

DOI  :  10.1016/j.neurobiolaging.2009.02.025

来源: Elsevier

【 摘 要 】

The amyloid-beta peptide (A beta) plays a central role in the pathogenesis of Alzheimer's disease (AD). The fibrillar form of A beta (fA beta) exerts toxic effects on neurons through mechanisms not well understood. We have shown that the aged primate cortex is selectively vulnerable to fA beta toxicity at low concentrations. In addition to neuronal loss, fA beta induced massive activation of microglia in the aged rhesus cortex. We now demonstrate that inhibition of microglia activation abolishes fA beta toxicity. Injection or pump delivery of macrophage/microglia inhibitory factor (MIF) significantly reduced activation of microglia and the volume of damage caused by fA beta. Microglia isolated from aged rhesus cortex produced substantial reactive oxygen species when stimulated by fA beta, which was inhibited by MIF in a dose-dependent manner. This is the first definitive in vivo demonstration that the fA beta-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 fA beta when compared with young microglia. (C) 2009 Elsevier Inc. All rights reserved.

【 授权许可】

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