IL-4-Induced Selective Clearance of Oligomeric β-Amyloid Peptide1-42 by Rat Primary Type 2 Microglia

A hallmark of immunopathology associated with Alzheimer's disease is the presence of activated microglia (MG) surrounding senile plaque deposition of beta-amyloid (A beta) peptides. A beta peptides are believed to be potent activators of MG, which leads to Alzheimer's disease pathology, but the role of MG subtypes in A beta clearance still remains unclear. In this study, we found that IL-4 treatment of rat primary-type 2 MG enhanced uptake and degradation of oligomeric A beta(1-42) (o-A beta(1-42)). IL-4 treatment induced significant expression of the scavenger receptor CD36 and the A beta-degrading enzymes neprilysin (NEP) and insulin-degrading enzyme (IDE) but reduced expression of certain other scavenger receptors. Of cytokines and stimulants tested, the anti-inflammatory cytokines IL-4 and IL-13 effectively enhanced CD36, NEP, and IDE. We demonstrated the CD36 contribution to IL-4-induced A beta clearance: Chinese hamster ovary cells overexpressing CD36 exhibited marked, dose-dependent degradation of 125 I-labeled o-A beta(1-42) compared with controls, the degradation being blocked by anti-CD36 Ab. Also, we found IL-4-induced clearance of o-A beta(1-42) in type 2 MG from CD36-expressing WKY/NCrj rats but not in cells from SHR/NCrJ rats with dysfunctional CD36 expression. NEP and IDE also contributed to IL-4-induced degradation of A beta(1-42), because their inhibitors, thiorphan and insulin, respectively, significantly suppressed this activity. IL-4-stimulated uptake and degradation of o-A beta(1-42) were selectively enhanced in type 2, but not type 1 MG that express CD40, which suggests that the two MG types may play different neuroimmuno-modulating roles in the A beta-overproducing brain. Thus, selective o-A beta(1-42) clearance, which is induced by IL-4, may provide an additional focus for developing strategies to prevent and treat Alzheimer's disease. The Journal of Immunology, 2008, 181: 6503-4513.