Alzheimer's disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner.

Autor: Staley HA; Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL, USA.; Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL, USA.; McKnight Brain Institute, University of Florida, Gainesville, FL, USA., Jernigan JE; Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL, USA.; Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL, USA.; McKnight Brain Institute, University of Florida, Gainesville, FL, USA., Bolen ML; Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL, USA.; Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL, USA.; McKnight Brain Institute, University of Florida, Gainesville, FL, USA., Titus AM; Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL, USA.; Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL, USA.; McKnight Brain Institute, University of Florida, Gainesville, FL, USA., Neighbarger N; Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL, USA.; Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL, USA.; McKnight Brain Institute, University of Florida, Gainesville, FL, USA., Cole C; Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL, USA.; Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL, USA.; McKnight Brain Institute, University of Florida, Gainesville, FL, USA., Menees KB; Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL, USA.; Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL, USA.; McKnight Brain Institute, University of Florida, Gainesville, FL, USA., Wallings RL; Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL, USA.; Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL, USA.; McKnight Brain Institute, University of Florida, Gainesville, FL, USA., Tansey MG; Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL, USA. mgtansey@UFL.edu.; Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL, USA. mgtansey@UFL.edu.; McKnight Brain Institute, University of Florida, Gainesville, FL, USA. mgtansey@UFL.edu.; Norman Fixel Institute for Neurological Diseases, University of Florida Health, Gainesville, FL, USA. mgtansey@UFL.edu.
Jazyk: angličtina
Zdroj: Journal of neuroinflammation [J Neuroinflammation] 2024 Nov 01; Vol. 21 (1), pp. 280. Date of Electronic Publication: 2024 Nov 01.
DOI: 10.1186/s12974-024-03271-9
Abstrakt: Genome-wide association studies have identified a protective mutation in the phospholipase C gamma 2 (PLCG2) gene which confers protection against Alzheimer's disease (AD)-associated cognitive decline. Therefore, PLCG2, which is primarily expressed in immune cells, has become a target of interest for potential therapeutic intervention. The protective allele, known as P522R, has been shown to be hyper-morphic in microglia, increasing phagocytosis of amyloid-beta (Aβ), and increasing the release of inflammatory cytokines. However, the effect of this protective mutation on peripheral tissue-resident macrophages, and the extent to which sex modifies this effect, has yet to be assessed. Herein, we show that peripheral macrophages carrying the P522R mutation do indeed show functional differences compared to their wild-type (WT) counterparts, however, these alterations occur in a sex-dependent manner. In macrophages from females, the P522R mutation increases lysosomal protease activity, cytokine secretion, and gene expression associated with cytokine secretion and apoptosis. In contrast, in macrophages from males, the mutation causes decreased phagocytosis and lysosomal protease activity, modest increases in cytokine secretion, and induction of gene expression associated with negative regulation of the immune response. Taken together, these results suggest that the mutation may be conferring different effects dependent on sex and cell type, and highlight the importance of considering sex as a biological variable when assessing the effects of genetic variants and implications for potential immune system-targeted therapies.
(© 2024. The Author(s).)
Databáze: MEDLINE
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