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Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer's disease.
Tsai, Andy P; Dong, Chuanpeng; Lin, Peter Bor-Chian; Oblak, Adrian L; Viana Di Prisco, Gonzalo; Wang, Nian; Hajicek, Nicole; Carr, Adam J; Lendy, Emma K; Hahn, Oliver; Atkins, Micaiah; Foltz, Aulden G; Patel, Jheel; Xu, Guixiang; Moutinho, Miguel; Sondek, John; Zhang, Qisheng; Mesecar, Andrew D; Liu, Yunlong; Atwood, Brady K; Wyss-Coray, Tony; Nho, Kwangsik; Bissel, Stephanie J; Lamb, Bruce T; Landreth, Gary E.
Afiliación
  • Tsai AP; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA; Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Dong C; Department of Medical and Molecular Genetics, Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
  • Lin PB; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Oblak AL; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Radiology & Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Viana Di Prisco G; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Wang N; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Radiology & Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Hajicek N; Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Carr AJ; Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Lendy EK; Department of Biochemistry, Purdue University, West Lafayette, IN, USA.
  • Hahn O; Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Atkins M; Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Foltz AG; Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Patel J; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Xu G; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Moutinho M; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Sondek J; Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Zhang Q; Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Mesecar AD; Department of Biochemistry, Purdue University, West Lafayette, IN, USA.
  • Liu Y; Department of Medical and Molecular Genetics, Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Atwood BK; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Wyss-Coray T; Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Nho K; Department of Radiology & Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Bissel SJ; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Lamb BT; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Landreth GE; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: glandret@iu.edu.
Immunity ; 56(9): 2121-2136.e6, 2023 09 12.
Article en En | MEDLINE | ID: mdl-37659412
Genetic association studies have demonstrated the critical involvement of the microglial immune response in Alzheimer's disease (AD) pathogenesis. Phospholipase C-gamma-2 (PLCG2) is selectively expressed by microglia and functions 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. Here, we identified a loss-of-function PLCG2 variant, PLCG2M28L, that confers an increased AD risk. PLCG2P522R attenuated disease in an amyloidogenic murine AD model, whereas PLCG2M28L exacerbated the plaque burden associated with altered phagocytosis and Aß clearance. The variants bidirectionally modulated disease pathology by inducing distinct transcriptional programs that identified microglial subpopulations associated with protective or detrimental phenotypes. These findings identify PLCG2M28L as a potential AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad de Alzheimer Tipo de estudio: Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Immunity Asunto de la revista: ALERGIA E IMUNOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad de Alzheimer Tipo de estudio: Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Immunity Asunto de la revista: ALERGIA E IMUNOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos