Microglial phagocytosis induced by fibrillar [beta]-amyloid is attenuated by oligomeric [beta]-amyloid: implications for Alzheimer's disease

Background Reactive microglia are associated with [beta]-amyloid (A[beta]) deposit and clearance in Alzhiemer's Disease (AD). Paradoxically, entocranial resident microglia fail to trigger an effective phagocytic response to clear A[beta] deposits although they mainly exist in an "activated" state. Oligomeric A[beta] (oA[beta]), a recent target in the pathogenesis of AD, can induce more potent neurotoxicity when compared with fibrillar A[beta] (fA[beta]). However, the role of the different A[beta] forms in microglial phagocytosis, induction of inflammation and oxidation, and subsequent regulation of phagocytic receptor system, remain unclear. Results We demonstrated that A[beta](1-42) fibrils, not A[beta](1-42) oligomers, increased the microglial phagocytosis. Intriguingly, the pretreatment of microglia with oA[beta](1-42) not only attenuated fA[beta](1-42)-triggered classical phagocytic response to fluorescent microspheres but also significantly inhibited phagocytosis of fluorescent labeled fA[beta](1-42). Compared with the fA[beta](1-42) treatment, the oA[beta](1-42) treatment resulted in a rapid and transient increase in interleukin 1[beta] (IL-1[beta]) level and produced higher levels of tumor necrosis factor-[alpha] (TNF-[alpha]), nitric oxide (NO), prostaglandin E.sub.2 (PGE.sub.2 ) and intracellular superoxide anion (SOA). The further results demonstrated that microglial phagocytosis was negatively correlated with inflammatory mediators in this process and that the capacity of phagocytosis in fA[beta](1-42)-induced microglia was decreased by IL-1[beta], lippolysaccharide (LPS) and tert-butyl hydroperoxide (t-BHP). The decreased phagocytosis could be relieved by pyrrolidone dithiocarbamate (PDTC), a nuclear factor-[kappa]B (NF-[kappa]B) inhibitor, and N-acetyl-L-cysteine (NAC), a free radical scavenger. These results suggest that the oA[beta]-impaired phagocytosis is mediated through inflammation and oxidative stress-mediated mechanism in microglial cells. Furthermore, oA[beta](1-42) stimulation reduced the mRNA expression of CD36, integrin [beta]1 (Itgb1), and Ig receptor Fc[gamma]RIII, and significantly increased that of formyl peptide receptor 2 (FPR2) and scavenger receptor class B1 (SRB1), compared with the basal level. Interestingly, the pre-stimulation with oA[beta](1-42) or the inflammatory and oxidative milieu (IL-1[beta], LPS or t-BHP) significantly downregulated the fA[beta](1-42)-induced mRNA over-expression of CD36, CD47 and Itgb1 recepto