Microglia activation mediates fibrillar amyloid-β toxicity in the aged primate cortex.
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.
Laboratory for Cognitive and Molecular Morphometry, Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
Elaine
E
Leung
Ling
L
Guo
Jing
J
Bu
Marie
M
Maloof
Joseph
J
El Khoury
Changiz
C
Geula
D000375:Aging; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D005260:Female; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D008253:Macaca mulatta; D017628:Microglia / Q000187:drug effects* / Q000502:physiology*; D009474:Neurons / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D014405:Tuftsin / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D006684:HLA-DR Antigens; D007155:Immunologic Factors; D017382:Reactive Oxygen Species; D014405:Tuftsin