CCR2/CCL2-mediated inflammation protects photoreceptor cells from amyloid-β-induced apoptosis

Age-related macular degeneration is characterized by the formation of drusen containing amyloid-beta (A beta) and the degeneration of photoreceptors. To explore the largely unknown role of A beta in the retina, we investigated the effects on photoreceptors of the oligomeric form of A beta(1-42). Subretinal injection of the A beta peptide induced misplaced expression of recoverin and synaptophysin in the photoreceptors, oxidative stress in their inner and outer segments, and finally apoptosis. A beta did not induce cell death in purified photoreceptor cell cultures, but did so in retinal cell cultures, thereby suggesting that the cellular environment plays a role in A beta-induced photoreceptor photoreceptor apoptosis. Subretinal injection of A beta was followed by activation and migration of microglial cells and then by photoreceptor apoptosis. Microglial cells phagocytosed rhodopsin-containing debris and A beta in the subretinal space. Quantitative RT-PCR allowed us to identify a specific gene expression profile associated with the A beta-induced progression of retinal degeneration and consistent with oxidative stress, inflammation, and an apoptotic program. The gene most highly upregulated in A beta-injected retinas was that for the chemokine CCL2, and its absence or that of its cognate receptor CCR2 greatly reduced migration of activated microglial cells to the site of retinal injury and profoundly worsened photoreceptor degeneration and disorganization of the retinal pigment epithelium in A beta-injected retinas. Our study pinpoints the roles of A beta and of CCL2/CCR2 axis-dependent inflammation in photoreceptor apoptosis. (C) 2011 Elsevier Inc. All rights reserved.