PLCγ2 deficiency compromises systemic immune tolerance and erodes myelin homeostasis while enhancing oxidative metabolism in the mouse brain

Gutierrez-Kuri, E.; Garcia-Rogers, J. L. M.; Perez, J.; Smith, S.; Kenwood, M. R.; Archuleta, K. S.; Xiao, Y.; Campos, G.; Barannikov, S.; Wang, H.; Pardo, S.; Romsdahl, T. B.; Miller, H.; Stowe, A. M.; William, R.; Goldberg, M.; Han, X.; Bieniek, K. F.; Weintraub, S. T.; Griffith, A. V.; Hopp, S. C.; Palavicini, J. P.

doi:10.64898/2026.07.13.738356

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bioRxiv · 10.64898/2026.07.13.738356

PLCγ2 deficiency compromises systemic immune tolerance and erodes myelin homeostasis while enhancing oxidative metabolism in the mouse brain

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Abstract

BackgroundPhospholipase C gamma-2 (PLC{gamma}2) catalyzes the hydrolysis of the membrane phosphatidylinositol-4,5-bisphosphate (PIP2) to form diacylglycerol (DAG) and inositol trisphosphate (IP3), feeding into diverse downstream signaling pathways. PLCG2 polymorphisms have been associated with reduced and/or increased risk of Alzheimers disease (AD) and related dementias, longevity, autoinflammation, and immune disorders. In the brain, PLC{gamma}2 is expressed in microglia, and other neuroimmune and vascular interface populations, yet its role in brain homeostasis remains incompletely defined. MethodsWe analyzed the brains of three-month-old Plcg2 wild-type (WT), heterozygous (Het KO) and homozygous knockout (Homo KO) littermate mice modeling human PLCG2 loss-of-function risk alleles linked to AD risk using a multiomic approach that included lipidomics, metabolomics, proteomics, and transcriptomics, together with immunofluorescence, as well as flow-cytometric profiling of peripheral and brain-draining immune compartments. ResultsPlcg2 deficiency substantially impaired early survival and produced splenomegaly without increasing total spleen cellularity, instead shifting spleen composition toward myeloid/innate-enriched cells and away from B cells, with expansion of age-associated B-cell (ABC-like) subsets and parallel reductions in CD4 and CD8 regulatory T cells in spleen and cervical lymph nodes. Brain lipidomics revealed selective depletion of PIP2, despite very low bulk PLC{gamma}2 protein abundance relative to other PLC family members. PLC{gamma}2 loss led to significant reductions in myelin-enriched lipid classes and myelin/paranode-associated proteins, accompanied by compensatory upregulation of oligodendrocyte/myelin genes, and modest shifts in microglial, lysosomal, complement, and oxidative metabolism pathways by NanoString and DIA-MS. Targeted acylcarnitine profiling demonstrated reprogramming of brain oxidative metabolism, with increased short-, medium-, and long-chain acylcarnitines and enrichment of mitochondrial matrix fatty-acid and amino-acid catabolic enzymes in Homo KO brains. ConclusionsLoss of PLC{gamma}2 installs a coordinated program that compromises systemic immune tolerance and subtly erodes central myelin and phosphoinositide homeostasis while enhancing brain oxidative metabolism, effects that extend beyond microglial phagocytic signaling and may underlie increased vulnerability to AD pathology and aging, providing a mechanistic framework for how PLCG2 variation may link systemic immune regulation, white-matter integrity, and neurodegenerative risk. LimitationsBecause constitutive Plcg2 Homo KO mice display high early mortality and intestinal vascular abnormalities, observed phenotypes may reflect developmental compensation and may not fully recapitulate protective human PLCG2 variants.

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Gutierrez-Kuri, E., Garcia-Rogers, J. L. M., Perez, J., Smith, S., Kenwood, M. R., Archuleta, K. S., Xiao, Y., Campos, G., Barannikov, S., Wang, H., Pardo, S., Romsdahl, T. B., Miller, H., Stowe, A. M., William, R., Goldberg, M., Han, X., Bieniek, K. F., Weintraub, S. T., Griffith, A. V., Hopp, S. C., Palavicini, J. P.. 2026-07-14. PLCγ2 deficiency compromises systemic immune tolerance and erodes myelin homeostasis while enhancing oxidative metabolism in the mouse brain. https://doi.org/10.64898/2026.07.13.738356

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