Glial-specific and inducible full body C3 deficiency does not affect amyloid pathology in the AppNL-G-F mouse model of Alzheimer’s disease

Background Alzheimer's disease (AD) is intricately linked with neuroinflammation, with the complement system, particularly C3, emerging as a critical player. However, research has been hampered by the reliance on classical germline C3 knockout and APP overexpressing mouse models, which do not allow to study temporal and cell-specific C3 effects, and do not accurately reflect the complexity of AD pathology. Methods In this study, we investigated the impact of conditional C3 deficiency on neuroinflammation and AD pathology, by generating microglia-specific (C3^mKO), astrocyte-specific (C3^aKO), and inducible full-body (C3^iKO) C3 knockout mice. To assess the role of C3 in both acute and chronic neuroinflammation, we employed an intracerebroventricular (ICV) LPS injection model in these mice alongside studies in the App^NL−G−F knock-in mouse model of AD upon aging and mild peripheral inflammation. Results Our results show that complement genes, including C3, are upregulated in microglia and astrocytes from 40 weeks old App^NL−G−F mice compared to their wildtype counterparts. Both microglia and astrocytes were shown to be significant sources of C3, as conditional C3 deficiency in either cell type led to decreased C3 expression and a dampened neuroinflammatory transcriptional response following ICV LPS injection. However, microglial- and astrocytic-specific C3 deficiency in App^NL−G−F mice did not affect total hippocampal C3 protein levels and amyloid plaque burden upon both 40 weeks of aging and in mild peripheral inflammation conditions. Also full-body C3 knockout, induced at the age of 8 weeks, did not alter Aβ pathology and glial activation, despite the complete removal of C3. Conclusions Our findings show that while C3 contributes to neuroinflammatory responses, its role in chronic AD-associated pathology is more complex than previously thought. Our study using novel cell-specific and inducible C3 knockout mice combined with the knock-in App^NL−G−F model provides new insights into the cell-specific roles of complement in AD, and highlights the need for further investigation into the complement system's involvement in neurodegenerative diseases.