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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,10,4]]},"abstract":"<jats:p>\n                    Biased G protein\u2013coupled receptor (GPCR) ligands, which preferentially activate G protein or \u03b2-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\u2019s disease (AD), biased GPCR signaling is a largely unexplored area of investigation in AD. Our previous work demonstrated that GPR3-mediated \u03b2-arrestin signaling modulates amyloid-\u03b2 (A\u03b2) generation\n                    <jats:italic>in\u00a0vitro<\/jats:italic>\n                    and that\n                    <jats:italic>Gpr3<\/jats:italic>\n                    deficiency ameliorates A\u03b2 pathology\n                    <jats:italic>in\u00a0vivo<\/jats:italic>\n                    . However,\n                    <jats:italic>Gpr3<\/jats:italic>\n                    -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\u2013biased GPR3 mouse model to investigate the physiological and pathophysiological consequences of selective elimination of GPR3-mediated \u03b2-arrestin signaling\n                    <jats:italic>in\u00a0vivo<\/jats:italic>\n                    . In contrast to\n                    <jats:italic>Gpr3<\/jats:italic>\n                    -deficient mice, G protein\u2013biased GPR3 mice do not display elevated anxiety levels, reduced fertility, or cognitive impairment. We further determined that G protein\u2013biased signaling reduces soluble A\u03b2 levels and leads to a decrease in the area and compaction of amyloid plaques in the preclinical\n                    <jats:italic>\n                      App\n                      <jats:sup>NL-G-F<\/jats:sup>\n                    <\/jats:italic>\n                    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\u2013biased GPR3 AD mice. Collectively, these studies indicate that GPR3-mediated G protein and \u03b2-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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2204828119","type":"journal-article","created":{"date-parts":[[2022,9,26]],"date-time":"2022-09-26T15:21:09Z","timestamp":1664205669000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":37,"title":["G protein\u2013biased GPR3 signaling ameliorates amyloid pathology in a preclinical Alzheimer\u2019s disease mouse model"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5799-1357","authenticated-orcid":false,"given":"Yunhong","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA,15260"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8324-0269","authenticated-orcid":false,"given":"Thais","family":"Rafael Guimar\u00e3es","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA,15260"},{"name":"Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA,15260"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3924-1464","authenticated-orcid":false,"given":"Nicholas","family":"Todd","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA,15260"},{"name":"Graduate Program in Molecular Pharmacology, University of Pittsburgh, Pittsburgh, PA, 15260"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn","family":"Ferguson","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology &amp; 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