Pharmacological inhibition of c5a-c5ar1 signaling decreases glial reactivity in a mouse model of Alzheimer's disease.

Abstract

The complement system, a powerful effector mechanism of the immune system, can be activated by fAβ, leading to the generation of C5a. Upon binding to its microglial receptor (C5aR1), C5a-C5aR1 signaling cascade contributes to neuroinflammation. Previous results have shown a beneficial effect of blocking C5a-C5aR1 in Alzheimer's disease (AD), either by a genetic ablation of C5aR1 or using a pharmacological approach. Here, we further examined the effect of a C5aR1 antagonist (PMX205) on the amyloid pathology and glial activation progression of a mouse model of AD. Tg2576 mice and WT littermates of 12 months of age were untreated or treated with PMX205 in the drinking water for 12 weeks. Mice were perfused and half of the brain followed a standard processing protocol for histological techniques. Double/triple immunohistochemistry with multiple markers for amyloid plaques, microglial cells, astrocytes and dystrophic neurites were assessed. Conventional and/or confocal microscopy were used to acquire the images, followed by image analysis and quantification. Tg2576 mice were characterized by an intense microglial and astroglial response, that increased with age and amyloid pathology. However, AD mice treated with PMX205 showed reduced expression of multiple microglial and astroglial markers, including Iba1, CD68, GFAP and C3 among others. Specifically, microglial-specific protein Iba1 was decreased up to 37% in the hippocampus, while C3 in astrocytes was reduced up to 69% in the hippocampus and 72% in the cortex. The decrease in glial reactivity was parallel to a significant reduction in amyloid plaques after treatment with PMX205. In addition, the presence of dystrophic neurites around amyloid plaques was also significantly reduced in the treated mice (48% reduction in the hippocampus and 57% reduction in the cortex), as shown by immunohistochemical quantification of Lamp1. Our results suggest a direct link between the pharmacological inhibition of C5aR1 and reduced neuroinflammation in an AD mouse model. Moreover, decreased number of dystrophic neurites could be an indicative of a neuroprotective function of PMX205. While the specific mechanism(s) underlying this protection still remains to be elucidated, modulation of C5a-C5aR1 signaling could serve as a potential therapeutic target for AD.