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Fus-depleted oligodendrocytes reduce neuronal damage and Alzheimer’s disease progression in the AppNL-G-F mouse

ABSTRACT: Oligodendrocytes provide myelination and metabolic support to neurons, but their contribution to Alzheimer's disease (AD) progression remains incompletely understood. To investigate the molecular effects of oligodendrocyte-specific Fus deletion, we performed single-cell RNA sequencing of hippocampal cells from AppNL-G-F (AD), AppNL-G-F/ Fusfl/fl/Cnpcre/+ (AD/cKO), Fusfl/fl/Cnpcre/+ (cKO), and Fusfl/fl (WT) mice. This dataset defines cell type-specific transcriptional profiles of hippocampal cells and identifies transcriptional changes associated with oligodendrocyte-specific Fus deletion in the context of Alzheimer's disease. These data provide a resource for investigating molecular pathways underlying oligodendrocyte function, glial interactions, and Alzheimer's disease pathogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE339460 | GEO | 2026/07/22

REPOSITORIES: GEO

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Project description: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 (C3mKO), astrocyte-specific (C3aKO), and inducible full-body (C3iKO) 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 AppNL-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 AppNL-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 AppNL-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 AppNL-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.

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Fus-depleted oligodendrocytes reduce neuronal damage and Alzheimer’s disease progression in the AppNL-G-F mouse

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