Genetic Variants of Phospholipase C-γ 2 Confer Altered Microglial Phenotypes and Differential Risk for Alzheimers Disease

Tsai, A. P.; Dong, C.; Lin, P. B.-C.; Oblak, A. L.; Viana Di Prisco, G.; Wang, N.; Hajicek, N.; Carr, A. J.; Lendy, E. K.; Hahn, O.; Atkins, M.; Foltz, A. G.; Patel, J.; Xu, G.; Moutinho, M.; Sondek, J.; Zhang, Q.; Mesecar, A. D.; Liu, Y.; Atwood, B. K.; Wyss-Coray, T.; Nho, K. T.; Bissel, S. J.; Lamb, B. T.; Landreth, G. E.

doi:10.1101/2022.12.08.519685

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bioRxiv · 10.1101/2022.12.08.519685

Genetic Variants of Phospholipase C-γ 2 Confer Altered Microglial Phenotypes and Differential Risk for Alzheimers Disease

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Abstract

Genetic association studies have demonstrated the critical involvement of the microglial immune response in Alzheimers disease (AD) pathogenesis. Phospholipase C-gamma-2 (PLCG2) is selectively expressed by microglia and acts in many immune receptor signaling pathways. In AD, PLCG2 is induced uniquely in plaque-associated microglia. A genetic variant of PLCG2, PLCG2P522R, is a mild hypermorph that attenuates AD risk. We report the identification of a PLCG2 variant, PLCG2M28L, associated with loss-of-function and confers increased AD risk. PLCG2P522R attenuates disease in an amyloidogenic murine AD model, whereas PLCG2M28L exacerbates the plaque burden associated with altered phagocytosis and A{beta} clearance. The variants bidirectionally modulate disease pathology by inducing distinct transcriptional programs that identify microglial subpopulations associated with protective or detrimental phenotypes. In summary, these findings identify PLCG2M28L as a new AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/519685v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@19f0aa6org.highwire.dtl.DTLVardef@74191eorg.highwire.dtl.DTLVardef@1d3a3forg.highwire.dtl.DTLVardef@db2a44_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIA genetic variant of PLCG2, M28L, is associated with an increased risk for Alzheimers disease (AD) C_LIO_LIIn an amyloidogenic AD mouse model, PLCG2M28L exacerbates disease pathogenesis C_LIO_LIConversely, PLCG2P522R, a protective PLCG2 variant, attenuates AD pathogenesis C_LIO_LIThe PLCG2 variants uniquely alter the microglial transcriptome and phenotypes C_LI

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Tsai, A. P., Dong, C., Lin, P. B.-C., Oblak, A. L., Viana Di Prisco, G., Wang, N., Hajicek, N., Carr, A. J., Lendy, E. K., Hahn, O., Atkins, M., Foltz, A. G., Patel, J., Xu, G., Moutinho, M., Sondek, J., Zhang, Q., Mesecar, A. D., Liu, Y., Atwood, B. K., Wyss-Coray, T., Nho, K. T., Bissel, S. J., Lamb, B. T., Landreth, G. E.. 2022-12-09. Genetic Variants of Phospholipase C-γ 2 Confer Altered Microglial Phenotypes and Differential Risk for Alzheimers Disease. https://doi.org/10.1101/2022.12.08.519685

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