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

Daskoulidou, Nikoleta, Shaw, Bethany, Zelek, Wioleta Milena and Morgan, Bryan Paul ORCID: https://orcid.org/0000-0003-4075-7676 2025. The Alzheimer's disease‐associated complement receptor 1 variant confers risk by impacting glial phagocytosis. Alzheimer's & Dementia: The Journal of the Alzheimer's Association 21 (7) , e70458. 10.1002/alz.70458

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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.

Item Type:	Article
Date Type:	Publication
Status:	In Press
Schools:	Schools > Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/
Publisher:	Wiley
ISSN:	1552-5260
Date of First Compliant Deposit:	14 July 2025
Date of Acceptance:	10 June 2025
Last Modified:	14 Jul 2025 15:30
URI:	https://orca.cardiff.ac.uk/id/eprint/179815

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