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Role of Microglial C5aR1 in the Arctic Alzheimer’s Disease Mouse Model

ABSTRACT: C5aR1, a receptor for the complement activation proinflammatory fragment, C5a, is primarily expressed on cells of the myeloid lineage, and to a lesser extent on endothelial cells and neurons in brain. Previous work demonstrated C5aR1 antagonist, PMX205, decreased amyloid pathology and suppressed cognitive deficits in Alzheimer Disease (AD) mouse models. In the Arctic AD mouse model, genetic deletion of C5aR1 prevented behavior deficits at 10 months. However, the molecular mechanisms of this protection has not been definitively demonstrated. To understand the role of microglial C5aR1 in the Arctic AD mouse model, we have taken advantage of the CX3CR1GFP and CCR2RFP reporter mice to distinguish microglia as GFP-positive and infiltrating monocytes as GFP and RFP positive, for subsequent transcriptome analysis on specifically sorted myeloid populations from wild type and AD mouse models. Immunohistochemical analysis of mice aged to 2, 5, 7 and 10 months showed no change in amyloid beta (Ab) deposition in the Arctic C5aR1 knockout (KO) mice relative to that seen in the Arctic mice. Of importance, no CCR2+ monocytes/macrophages were found near the plaques in the Arctic brain with or without C5aR1. RNA-seq analysis on microglia from these mice identified inflammation related genes as differentially expressed, with increased expression in the Arctic mice relative to wildtype and decreased expression in the Arctic/C5aR1KO relative to Arctic. In addition, phagosomal-lysosomal proteins and protein degradation pathways that were increased in the Arctic mice were further increased in the Arctic/C5aR1KO mice. These data are consistent with a microglial polarization state with restricted induction of inflammatory genes and enhancement of clearance pathways.

ORGANISM(S): Mus musculus

PROVIDER: GSE93824 | GEO | 2017/10/10

SECONDARY ACCESSION(S): PRJNA362540

REPOSITORIES: GEO

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Project description:The complement system is part of the innate immune system that works to clear pathogens and cellular debris. In the central nervous system (CNS) complement activation can promote synaptic pruning clearance of neuronal blebs recruitment of phagocytes and protection from pathogens. However in a neuropathologic environment complement activation may contribute to inflammatory pathways neuronal dysfunction and in the Alzheimer’s disease (AD) brain cognitive decline. If complement activation proceeds to the cleavage of C5 and thus generation of C5a engagement of C5a with the receptor C5aR1 can instigate a feed-forward loop of inflammation injury and neuronal death thus making this molecule a potential target for modulation in AD therapeutics. The Arctic (Arc) AD mouse model known to rapidly accumulate fibrillar amyloid plaques was crossed to a model that lacks the receptor for C5a (ArcC5aR1KO) or to a transgenic mouse that generates C5a under the GFAP promoter (ArcC5a+). ArcticC5a+ mice showed accelerated loss of spatial memory compared to Arc mice. While eliminating C5aR1 did not alter amyloid plaque accumulation in this AD model C5aR1KO delayed or prevented the expression of important AD-associated genes in the hippocampus indicating a separation between those genes induced by amyloid plaques and those influenced by C5a-C5aR1 signaling. C5ar1 deletion also reduced/delayed the expression of select pan-reactive and A1 reactive astrocyte genes. ArcC5aR1KO showed delayed expression of genes enriched for biological processes that are significant in the AD context such as regulation of inflammatory signaling microglial cell activation astrocyte migration and lysosome pathway. Interestingly overexpression of C5a also delayed the increase of some AD- complement and astrocyte-associated genes perhaps mediated by C5aR2 and emphasizing the importance of selectively suppressing C5aR1. Immunohistochemical investigation further confirmed that modulation of C5a-C5aR1 either delayed or reduced some reactive microglial markers in the Arc hippocampus including CD11b and CD11c. These results suggest that C5a-C5aR1 signaling in the context of AD largely exerts its effects by suppressing those microglial activation pathways that accelerate disease enhancing pathways. Given the highly focused modulation of a common driver of neurotoxicity pharmacological inhibition of this C5aR1 signaling pathway is a promising therapeutic strategy to treat AD.

Project description:GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer's disease. Reactive astrocytes with an increased expression of intermediate filament (IF) proteins Glial Fibrillary Acidic Protein (GFAP) and Vimentin (VIM) surround amyloid plaques in Alzheimer's disease (AD). The functional consequences of this upregulation are unclear. To identify molecular pathways coupled to IF regulation in reactive astrocytes, and to study the interaction with microglia, we examined WT and APPswe/PS1dE9 (AD) mice lacking either GFAP, or both VIM and GFAP, and determined the transcriptome of cortical astrocytes and microglia from 15- to 18-month-old mice. Genes involved in lysosomal degradation (including several cathepsins) and in inflammatory response (including Cxcl5, Tlr6, Tnf, Il1b) exhibited a higher AD-induced increase when GFAP, or VIM and GFAP, were absent. The expression of Aqp4 and Gja1 displayed the same pattern. The downregulation of neuronal support genes in astrocytes from AD mice was absent in GFAP/VIM null mice. In contrast, the absence of IFs did not affect the transcriptional alterations induced by AD in microglia, nor was the cortical plaque load altered. Visualizing astrocyte morphology in GFAP-eGFP mice showed no clear structural differences in GFAP/VIM null mice, but did show diminished interaction of astrocyte processes with plaques. Microglial proliferation increased similarly in all AD groups. In conclusion, absence of GFAP, or both GFAP and VIM, alters AD-induced changes in gene expression profile of astrocytes, showing a compensation of the decrease of neuronal support genes and a trend for a slightly higher inflammatory expression profile. However, this has no consequences for the development of plaque load, microglial proliferation, or microglial activation. 2 cell types from 6 conditions: cortical microglia and cortical astrocytes from 15-18 month old APPswe/PS1dE9 mice compared to wildtype littermates. Biological replicates: microglia from APPswe/PS1dE9, N=7, microglia from WT, N=7, astrocytes from APPswe/PS1dE9, N=4, microglia from WT, N=4

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Role of Microglial C5aR1 in the Arctic Alzheimer’s Disease Mouse Model

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