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G protein-biased GPR3 signaling ameliorates amyloid pathology in a preclinical Alzheimer's disease mouse model.
Huang, Yunhong; Rafael Guimarães, Thais; Todd, Nicholas; Ferguson, Carolyn; Weiss, Kathryn M; Stauffer, Fiona R; McDermott, Breanne; Hurtle, Bryan T; Saito, Takashi; Saido, Takaomi C; MacDonald, Matthew L; Homanics, Gregg E; Thathiah, Amantha.
Afiliação
  • Huang Y; Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA,15260.
  • Rafael Guimarães T; Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA,15260.
  • Todd N; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA,15260.
  • Ferguson C; Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA,15260.
  • Weiss KM; Graduate Program in Molecular Pharmacology, University of Pittsburgh, Pittsburgh, PA, 15260.
  • Stauffer FR; Department of Anesthesiology & Perioperative Medicine, University of Pittsburgh, Pittsburgh, PA, 15260.
  • McDermott B; Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA,15260.
  • Hurtle BT; Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA,15260.
  • Saito T; Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA,15260.
  • Saido TC; Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA,15260.
  • MacDonald ML; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA,15260.
  • Homanics GE; Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Science, Nagoya, 467-8601, Japan.
  • Thathiah A; Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Saitama, 351-0198, Japan.
Proc Natl Acad Sci U S A ; 119(40): e2204828119, 2022 10 04.
Article em En | MEDLINE | ID: mdl-36161942
ABSTRACT
Biased G protein-coupled receptor (GPCR) ligands, which preferentially activate G protein or ß-arrestin signaling pathways, are leading to the development of drugs with superior efficacy and reduced side effects in heart disease, pain management, and neuropsychiatric disorders. Although GPCRs are implicated in the pathophysiology of Alzheimer's disease (AD), biased GPCR signaling is a largely unexplored area of investigation in AD. Our previous work demonstrated that GPR3-mediated ß-arrestin signaling modulates amyloid-ß (Aß) generation in vitro and that Gpr3 deficiency ameliorates Aß pathology in vivo. However, Gpr3-deficient mice display several adverse phenotypes, including elevated anxiety-like behavior, reduced fertility, and memory impairment, which are potentially associated with impaired G protein signaling. Here, we generated a G protein-biased GPR3 mouse model to investigate the physiological and pathophysiological consequences of selective elimination of GPR3-mediated ß-arrestin signaling in vivo. In contrast to Gpr3-deficient mice, G protein-biased GPR3 mice do not display elevated anxiety levels, reduced fertility, or cognitive impairment. We further determined that G protein-biased signaling reduces soluble Aß levels and leads to a decrease in the area and compaction of amyloid plaques in the preclinical AppNL-G-F AD mouse model. The changes in amyloid pathology are accompanied by robust microglial and astrocytic hypertrophy, which suggest a protective glial response that may limit amyloid plaque development in G protein-biased GPR3 AD mice. Collectively, these studies indicate that GPR3-mediated G protein and ß-arrestin signaling produce discrete and separable effects and provide proof of concept for the development of safer GPCR-targeting therapeutics with more directed pharmacological action for AD.
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Doença de Alzheimer / Amiloidose Limite: Animals Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Doença de Alzheimer / Amiloidose Limite: Animals Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2022 Tipo de documento: Article