{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T14:37:25Z","timestamp":1792507045936,"version":"4.5.0"},"reference-count":65,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"693","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2023,4,26]]},"abstract":"<jats:p>Sleep loss is associated with cognitive decline in the aging population and is a risk factor for Alzheimer\u2019s disease (AD). Considering the crucial role of immunomodulating genes such as that encoding the triggering receptor expressed on myeloid cells type 2 (TREM2) in removing pathogenic amyloid-\u03b2 (A\u03b2) plaques and regulating neurodegeneration in the brain, our aim was to investigate whether and how sleep loss influences microglial function in mice. We chronically sleep-deprived wild-type mice and the 5xFAD mouse model of cerebral amyloidosis, expressing either the humanized TREM2 common variant, the loss-of-function R47H AD-associated risk variant, or without TREM2 expression. Sleep deprivation not only enhanced TREM2-dependent A\u03b2 plaque deposition compared with 5xFAD mice with normal sleeping patterns but also induced microglial reactivity that was independent of the presence of parenchymal A\u03b2 plaques. We investigated lysosomal morphology using transmission electron microscopy and found abnormalities particularly in mice without A\u03b2 plaques and also observed lysosomal maturation impairments in a TREM2-dependent manner in both microglia and neurons, suggesting that changes in sleep modified neuro-immune cross-talk. Unbiased transcriptome and proteome profiling provided mechanistic insights into functional pathways triggered by sleep deprivation that were unique to TREM2 and A\u03b2 pathology and that converged on metabolic dyshomeostasis. Our findings highlight that sleep deprivation directly affects microglial reactivity, for which TREM2 is required, by altering the metabolic ability to cope with the energy demands of prolonged wakefulness, leading to further A\u03b2 deposition, and underlines the importance of sleep modulation as a promising future therapeutic approach.<\/jats:p>","DOI":"10.1126\/scitranslmed.ade6285","type":"journal-article","created":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T13:58:24Z","timestamp":1682517504000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":128,"title":["Sleep deprivation exacerbates microglial reactivity and A\u03b2 deposition in a\n                    <i>TREM2<\/i>\n                    -dependent manner in mice"],"prefix":"10.1126","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5807-190X","authenticated-orcid":true,"given":"Samira","family":"Parhizkar","sequence":"first","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer\u2019s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace","family":"Gent","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer\u2019s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0547-9463","authenticated-orcid":true,"given":"Yun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer\u2019s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA."},{"name":"Department of Pathology and Immunology, Washington University, St. Louis, MO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Rensing","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer\u2019s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maud","family":"Gratuze","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer\u2019s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2027-6851","authenticated-orcid":true,"given":"Gregory","family":"Strout","sequence":"additional","affiliation":[{"name":"Washington University Center for Cellular Imaging, Washington University School of Medicine, St. Louis, MO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5918-4834","authenticated-orcid":true,"given":"Sanja","family":"Sviben","sequence":"additional","affiliation":[{"name":"Washington University Center for Cellular Imaging, Washington University School of Medicine, St. Louis, MO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6362-0141","authenticated-orcid":true,"given":"Eric","family":"Tycksen","sequence":"additional","affiliation":[{"name":"Genome Technology Access Center, Washington University School of Medicine, St. Louis, MO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7046-4378","authenticated-orcid":true,"given":"Qiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University Medical School, St. Louis, MO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3949-9801","authenticated-orcid":true,"given":"Petra Erdmann","family":"Gilmore","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University Medical School, St. Louis, MO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2368-8859","authenticated-orcid":true,"given":"Robert","family":"Sprung","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University Medical School, St. Louis, MO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2199-0456","authenticated-orcid":true,"given":"Jim","family":"Malone","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University Medical School, St. Louis, MO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer\u2019s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5937-0212","authenticated-orcid":true,"given":"Javier","family":"Remolina Serrano","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer\u2019s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Bao","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer\u2019s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8907-5858","authenticated-orcid":true,"given":"Choonghee","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer\u2019s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6418-3809","authenticated-orcid":true,"given":"Chanung","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer\u2019s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3227-1641","authenticated-orcid":true,"given":"Eric","family":"Landsness","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer\u2019s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7907-3602","authenticated-orcid":true,"given":"James","family":"Fitzpatrick","sequence":"additional","affiliation":[{"name":"Washington University Center for Cellular Imaging, Washington University School of Medicine, St. Louis, MO, USA."},{"name":"Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, USA."},{"name":"Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA."},{"name":"Department of Biomedical Engineering, McKelvey School of Engineering, Washington University in St. Louis, St. Louis, MO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer\u2019s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0753-7594","authenticated-orcid":true,"given":"Reid","family":"Townsend","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University Medical School, St. Louis, MO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5222-4987","authenticated-orcid":true,"given":"Marco","family":"Colonna","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University, St. Louis, MO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8334-5893","authenticated-orcid":true,"given":"Robert E.","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University, St. Louis, MO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3400-0856","authenticated-orcid":true,"given":"David M.","family":"Holtzman","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer\u2019s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22354-2"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1101\/lm.031674.113"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1241224"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-016-0138-8"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3981-16.2017"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aax7331"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/cns.13218"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav2546"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1180962"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx148"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-170032"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201704-0704OC"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25117"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000004171"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4035"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2013.2334"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aau6550"},{"key":"e_1_3_3_19_2","first-page":"1537","article-title":"Self-reported sleep and \u03b2-amyloid deposition in community-dwelling older adults","volume":"70","author":"Spira A. P.","year":"2013","unstructured":"A. P. Spira, A. A. Gamaldo, Y. An, M. N. Wu, E. M. Simonsick, M. Bilgel, Y. Zhou, D. F. Wong, L. Ferrucci, S. M. Resnick, Self-reported sleep and \u03b2-amyloid deposition in community-dwelling older adults. JAMA Neurol. 70, 1537\u20131543 (2013).","journal-title":"JAMA Neurol."},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.525970"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2020.105031"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.16424"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2017.02.008"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aag2590"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.09.001"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20190980"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2010.08.014"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00021.2005"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20171529"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.02.042"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0296-9"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-019-0433-0"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0695-9"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20180653"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2017.08.008"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.05.018"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1202-06.2006"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3004291"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2010.05.027"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-9-20"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.07.023"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.4103\/1673-5374.264444"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1705240114"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-020-00583-9"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1860-14.2014"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20141788"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.12.007"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2777-8"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2801"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aad3650"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2017.09.011"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.09-132043"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11357-011-9333-2"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20160493"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jagp.2013.04.015"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.01.049"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0224642"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2015.11.004"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-60761-744-0_2"},{"key":"e_1_3_3_60_2","first-page":"960","article-title":"A technique for serial collection of cerebrospinal fluid from the cisterna magna in mouse","author":"Liu L.","year":"2008","unstructured":"L. Liu, K. Duff, A technique for serial collection of cerebrospinal fluid from the cisterna magna in mouse. J. Vis. Exp., 960 (2008).","journal-title":"J. Vis. Exp."},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1021\/pr4010019"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M111.011445"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.TIR118.000900"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.21105\/joss.01686"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v032.i06"},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.ade6285","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T12:12:00Z","timestamp":1705407120000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.ade6285"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,26]]},"references-count":65,"journal-issue":{"issue":"693","published-print":{"date-parts":[[2023,4,26]]}},"alternative-id":["10.1126\/scitranslmed.ade6285"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.ade6285","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,26]]},"assertion":[{"value":"2022-08-31","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-04-07","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-04-26","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eade6285"}}