The Alzheimer's disease‐associated complement receptor 1 variant confers risk by impacting glial phagocytosis

Abstract INTRODUCTION Genome‐wide association studies have implicated complement in Alzheimer's disease (AD). The CR1*2 variant of complement receptor 1 (CR1; CD35), confers increased AD risk. We confirmed CR1 expression on glial cells; however, how CR1 variants influence AD risk remains unclear. METHODS Induced pluripotent stem cell‐derived microglia and astrocytes were generated from donors homozygous for the common CR1 variants (CR1*1/CR1*1;CR1*2/CR1*2). CR1 expression was quantified and phagocytic activity assessed using diverse targets ( Escherichia coli bioparticles, amyloid β aggregates, and synaptoneurosomes), with or without serum opsonization. RESULTS Expression of CR1*1 was significantly higher than CR1*2 on glial lines. Phagocytosis for all targets was markedly enhanced following serum opsonization, attenuated by Factor I‐depletion, demonstrating CR1 requirement for C3b processing. CR1*2‐expressing glia showed significantly enhanced phagocytosis of all opsonized targets compared to CR1*1‐expressing cells. DISCUSSION CR1 is critical for glial phagocytosis of opsonized targets. CR1*2, despite lower expression, enhances glial phagocytosis, providing mechanistic explanation of increased AD risk. Highlights Induced pluripotent stem cell (iPSC)‐derived glia from individuals expressing the Alzheimer's disease (AD) risk variant complement receptor (CR) 1*2 exhibit lower CR1 expression compared to those from donors expressing the non‐risk form CR1*1. The iPSC‐derived glia from individuals expressing the AD risk variant CR1*2 exhibit enhanced phagocytic activity for opsonized bacterial particles, amyloid‐β aggregates and human synaptoneurosomes compared to those from donors expressing the non‐risk form CR1*1. We suggest that expression of the CR1*2 variant confers risk of AD by enhancing the phagocytic capacity of glia for opsonized targets.