{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T10:41:31Z","timestamp":1789382491025,"version":"build-2803163510"},"reference-count":52,"publisher":"Society for Neuroscience","issue":"13","license":[{"start":{"date-parts":[[2004,9,30]],"date-time":"2004-09-30T00:00:00Z","timestamp":1096502400000},"content-version":"vor","delay-in-days":183,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2004,3,31]]},"abstract":"<jats:p>Overwhelming evidence indicates that the effects of \u03b2-amyloid (A\u03b2) are dose dependent both<jats:italic>in vitro<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>, which implies that A\u03b2 is not directly detrimental to brain cells until it reaches a threshold concentration. In an effort to understand early Alzheimer's disease (AD) pathogenesis, this study focused on the effects of subthreshold soluble A\u03b2 and the underlying molecular mechanisms in murine microglial cells and an AD transgenic mouse model. We found that there were two phases of dose-dependent A\u03b2 effects on microglial cells: at the threshold of 5 \u03bc<jats:sc>m<\/jats:sc>and above, A\u03b2 directly induced tumor necrosis factor-\u03b1 (TNF-\u03b1) release, and at subthreshold doses, A\u03b2 indirectly potentiated TNF-\u03b1 release induced by certain G-protein-coupled receptor (GPCR) activators. Mechanistic studies revealed that subthreshold A\u03b2 pretreatment<jats:italic>in vitro<\/jats:italic>reduced membrane GPCR kinase-2\/5 (GRK2\/5), which led to retarded GPCR desensitization, prolonged GPCR signaling, and cellular hyperactivity to GPCR agonists. Temporal analysis in an early-onset AD transgenic model, CRND8 mice, revealed that the membrane (functional) GRK2\/5 in brain cortices were significantly reduced. More importantly, such a GRK abnormality took place before cognitive decline and changed in a manner corresponding with the mild to moderate soluble A\u03b2 accumulation in these transgenic mice. Together, this study not only discovered a novel link between subthreshold A\u03b2 and GRK dysfunction, it also demonstrated that the GRK abnormality<jats:italic>in vivo<\/jats:italic>occurs at prodromal and early stages of AD.<\/jats:p>","DOI":"10.1523\/jneurosci.4856-03.2004","type":"journal-article","created":{"date-parts":[[2004,3,31]],"date-time":"2004-03-31T20:47:59Z","timestamp":1080766079000},"page":"3444-3452","source":"Crossref","is-referenced-by-count":64,"title":["Abnormality of G-Protein-Coupled Receptor Kinases at Prodromal and Early Stages of Alzheimer's Disease: An Association with Early \u03b2-Amyloid Accumulation"],"prefix":"10.1523","volume":"24","author":[{"given":"Zhiming","family":"Suo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce A.","family":"Citron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwendolyn T.","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barry W.","family":"Festoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2004,3,31]]},"reference":[{"key":"2023041303060656000_24.13.3444.1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(92)90065-F"},{"key":"2023041303060656000_24.13.3444.2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.11.7565"},{"key":"2023041303060656000_24.13.3444.3","first-page":"21562","volume":"15","year":"2001","journal-title":"J Biol Chem"},{"key":"2023041303060656000_24.13.3444.4","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1111\/j.1749-6632.1997.tb48459.x","volume":"826","year":"1997","journal-title":"Ann NY Acad Sci"},{"key":"2023041303060656000_24.13.3444.5","doi-asserted-by":"publisher","DOI":"10.1006\/exnr.1997.6743"},{"key":"2023041303060656000_24.13.3444.6","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(98)01170-3"},{"key":"2023041303060656000_24.13.3444.7","doi-asserted-by":"publisher","DOI":"10.1002\/ddr.10321"},{"key":"2023041303060656000_24.13.3444.8","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1111\/j.1749-6632.1996.tb39072.x","volume":"786","year":"1996","journal-title":"Ann NY Acad Sci"},{"key":"2023041303060656000_24.13.3444.9","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)81048-X"},{"key":"2023041303060656000_24.13.3444.10","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(03)00192-2"},{"key":"2023041303060656000_24.13.3444.11","doi-asserted-by":"publisher","DOI":"10.1038\/ni777"},{"key":"2023041303060656000_24.13.3444.12","doi-asserted-by":"publisher","DOI":"10.1021\/bi9902236"},{"key":"2023041303060656000_24.13.3444.13","doi-asserted-by":"publisher","DOI":"10.1126\/science.1072994"},{"key":"2023041303060656000_24.13.3444.14","doi-asserted-by":"crossref","first-page":"8876","DOI":"10.1523\/JNEUROSCI.19-20-08876.1999","volume":"19","year":"1999","journal-title":"J Neurosci"},{"key":"2023041303060656000_24.13.3444.15","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(98)00162-8"},{"key":"2023041303060656000_24.13.3444.16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/bj3110001","volume":"311","year":"1995","journal-title":"Biochem J"},{"key":"2023041303060656000_24.13.3444.17","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1993.tb23024.x"},{"key":"2023041303060656000_24.13.3444.18","doi-asserted-by":"publisher","DOI":"10.1124\/mol.63.1.9"},{"key":"2023041303060656000_24.13.3444.19","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)65184-X"},{"key":"2023041303060656000_24.13.3444.20","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-4580(01)00289-5"},{"key":"2023041303060656000_24.13.3444.21","doi-asserted-by":"publisher","DOI":"10.1038\/374647a0"},{"key":"2023041303060656000_24.13.3444.22","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.10.6483"},{"key":"2023041303060656000_24.13.3444.23","doi-asserted-by":"crossref","first-page":"3014","DOI":"10.1046\/j.1432-1033.2002.02976.x","volume":"269","year":"2002","journal-title":"Eur J Biochem"},{"key":"2023041303060656000_24.13.3444.24","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00022.2002"},{"key":"2023041303060656000_24.13.3444.25","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1523\/JNEUROSCI.20-01-00251.2000","volume":"20","year":"2000","journal-title":"J Neurosci"},{"key":"2023041303060656000_24.13.3444.26","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-4580(00)82162-4"},{"key":"2023041303060656000_24.13.3444.27","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.67.1.653"},{"key":"2023041303060656000_24.13.3444.28","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1096\/fasebj.9.2.7781920","volume":"9","year":"1995","journal-title":"FASEB J"},{"key":"2023041303060656000_24.13.3444.29","doi-asserted-by":"publisher","DOI":"10.1093\/ilar.43.2.89"},{"key":"2023041303060656000_24.13.3444.30","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1993.tb23023.x"},{"key":"2023041303060656000_24.13.3444.31","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/S0167-4889(00)00088-4","volume":"1498","year":"2000","journal-title":"Biochim Biophys Acta"},{"key":"2023041303060656000_24.13.3444.32","doi-asserted-by":"crossref","first-page":"2286","DOI":"10.1111\/j.1471-4159.1993.tb07471.x","volume":"61","year":"1993","journal-title":"J Neurochem"},{"key":"2023041303060656000_24.13.3444.33","doi-asserted-by":"crossref","first-page":"R897","DOI":"10.1152\/ajpregu.2001.280.3.R897","volume":"280","year":"2001","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"2023041303060656000_24.13.3444.34","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M004589200"},{"key":"2023041303060656000_24.13.3444.35","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/S0002-9440(10)65643-X","volume":"153","year":"1998","journal-title":"Am J Pathol"},{"key":"2023041303060656000_24.13.3444.36","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.16.12200"},{"key":"2023041303060656000_24.13.3444.37","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(97)00383-1"},{"key":"2023041303060656000_24.13.3444.38","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(98)00814-3"},{"key":"2023041303060656000_24.13.3444.39","first-page":"381","volume":"1","year":"1998","journal-title":"Alzheimers Rep"},{"key":"2023041303060656000_24.13.3444.40","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2000.tb06363.x"},{"key":"2023041303060656000_24.13.3444.41","doi-asserted-by":"publisher","DOI":"10.1046\/j.0022-3042.2001.00745.x"},{"key":"2023041303060656000_24.13.3444.42","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M302137200"},{"key":"2023041303060656000_24.13.3444.43","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M301406200"},{"key":"2023041303060656000_24.13.3444.44","doi-asserted-by":"crossref","unstructured":"Suo Z, Citron BA, Festoff BW (2004) Thrombin: a proinflammatory mediator of central nervous system trauma and neurodegenerative disorders. Current Drug Targets Inflam Allerg, in press.","DOI":"10.2174\/1568010043483953"},{"key":"2023041303060656000_24.13.3444.45","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2002.01062.x"},{"key":"2023041303060656000_24.13.3444.46","doi-asserted-by":"publisher","DOI":"10.1038\/380168a0"},{"key":"2023041303060656000_24.13.3444.47","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.13.7440"},{"key":"2023041303060656000_24.13.3444.48","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-0082(99)00055-6"},{"key":"2023041303060656000_24.13.3444.49","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.35.22364"},{"key":"2023041303060656000_24.13.3444.50","doi-asserted-by":"publisher","DOI":"10.1038\/416535a"},{"key":"2023041303060656000_24.13.3444.51","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.31.2.534"},{"key":"2023041303060656000_24.13.3444.52","doi-asserted-by":"publisher","DOI":"10.1126\/science.2474201"}],"container-title":["The Journal of Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1523\/JNEUROSCI.4856-03.2004","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,13]],"date-time":"2023-04-13T16:02:02Z","timestamp":1681401722000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jneurosci.org\/lookup\/doi\/10.1523\/JNEUROSCI.4856-03.2004"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,3,31]]},"references-count":52,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2004,3,31]]},"published-print":{"date-parts":[[2004,3,31]]}},"alternative-id":["10.1523\/JNEUROSCI.4856-03.2004"],"URL":"https:\/\/doi.org\/10.1523\/jneurosci.4856-03.2004","relation":{},"ISSN":["0270-6474","1529-2401"],"issn-type":[{"value":"0270-6474","type":"print"},{"value":"1529-2401","type":"electronic"}],"subject":[],"published":{"date-parts":[[2004,3,31]]}}}