Microglia are the principle immune effector and phagocytic cells in the CNS. These cells are associated with fibrillar ␤-amyloid (fA␤)-containing plaques found in the brains of Alzheimer's disease (AD) patients. The plaque-associated microglia undergo a phenotypic conversion into an activated phenotype and are responsible for the development of a focal inflammatory response that exacerbates and accelerates the disease process. Paradoxically, despite the presence of abundant activated microglia in the brain of AD patients, these cells fail to mount a phagocytic response to A␤ deposits but can efficiently phagocytose A␤ fibrils and plaques in vitro.We report that exposure of microglia to fA␤ in vitro induces phagocytosis through mechanisms distinct from those used by the classical phagocytic receptors, the Ig receptors (FcR␥I and Fc␥RIII) or complement receptors. Microglia interact with fA␤ through a recently characterized A␤ cell surface receptor complex comprising the B-class scavenger receptor CD36, ␣ 6 ␤ 1 integrin, and CD47 (integrin-associated protein). Antagonists specific for each component of the receptor complex blocks fA␤-stimulated phagocytosis. These data demonstrated that engagement of this ensemble of receptors is required for induction of phagocytosis. The phagocytic response stimulated by this receptor complex is driven principally by a ␤ 1 integrin-linked process that is morphologically and mechanistically distinct from the classical type I and type II phagocytic mechanisms. These data provide evidence for phagocytic uptake of fA␤ through a receptor-mediated, nonclassical phagocytic mechanism.

Malignant astrocytomas are among the most common brain tumours and few therapeutic options exist. It has recently been recognized that the ligand-activated nuclear receptor PPARc can regulate cellular proliferation and induce apoptosis in different malignant cells. We report the effect of three structurally different PPARc agonists inducing apoptosis in human (U87MG and A172) and rat (C6) glioma cells. The PPARc agonists ciglitazone, LY171 833 and prostaglandin-J2, but not the PPARa agonist WY14643, inhibited proliferation and induced cell death. PPARc agonist-induced cell death was characterized by DNA fragmentation and nuclear condensation, as well as inhibited by the synthetic receptor-antagonist bisphenol A diglycidyl ether (BADGE). In contrast, primary murine astrocytes were not affected by PPARc agonist treatment. The apoptotic death in the glioma cell lines treated with PPARc agonists was correlated with the transient up-regulation of Bax and Bad protein levels. Furthermore, inhibition of Bax expression by specific antisense oligonucleotides protected glioma cells against PPARc-mediated apoptosis, indicating an essential role of Bax in PPARc-induced apoptosis. However, PPARc agonists not only induced apoptosis but also caused redifferentiation as indicated by outgrowth of long processes and expression of the redifferentiation marker N-cadherin in response to PPARc agonists. Taken together, treatment of glioma cells with PPARc agonists may hold therapeutic potential for the treatment of gliomas.