{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T06:03:15Z","timestamp":1782280995142,"version":"3.54.5"},"posted":{"date-parts":[[2025,4,4]]},"group-title":"Neuroscience","reference-count":73,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T00:00:00Z","timestamp":1743724800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Circadian disruption has long been appreciated as a downstream consequence of Alzheimer\u2019s Disease in humans. However, an upstream role for behavioral circadian disruption in regulating AD pathology remains an open question.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    To determine the role of the central circadian clock in the suprachiasmatic nucleus (SCN) in regulating amyloid pathology, we generated mice harboring deletion of the critical clock gene\n                    <jats:italic>Bmal1<\/jats:italic>\n                    in GABAergic neurons using VGAT-iCre, which is expressed in &gt;95% of SCN cells, and crossed this line to the 5xFAD amyloid mouse model. To examine the role of the light-dark cycle in this process, we aged these mice in either regular 12:12 light-dark (LD) or constant darkness (DD) conditions. Transcriptional, behavioral, and physiological rhythms were examined in VGAT-iCre;\n                    <jats:italic>Bmal1<\/jats:italic>\n                    <jats:sup>fl\/fl<\/jats:sup>\n                    ; 5xFAD (VGAT-BMAL1KO;5xFAD) mice under varying light conditions. Amyloid plaque deposition, peri-plaque tau phosphorylation, glial activation, and transcriptomic changes were examined.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    VGAT-BMAL1KO;5xFAD mice showed loss of SCN BMAL1 expression and severe disruption of behavioral rhythms in both LD and DD, with loss of day-night rhythms in consolidated sleep and blunting of rhythmic clock gene expression in the brain. Surprisingly, VGAT-BMAL1KO;5xFAD mice kept under LD showed reduced total plaque accumulation and peri-plaque tau phosphorylation, compared to Cre-negative controls. These changes were gated by the light-dark cycle, as they were absent in VGAT-BMAL1KO;5xFAD mice kept in DD conditions. Total plaque accumulation was also reduced in control 5xFAD mice kept in DD as compared to LD, suggesting a general effect of light-dark cycle on amyloid aggregation. Expression of murine presenilin 1 (\n                    <jats:italic>Psen1<\/jats:italic>\n                    ), as well as amyloidogenic cleavage of amyloid precursor protein, were suppressed in VGAT-BMAL1KO;5xFAD specifically under LD conditions.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>In 5xFAD mice, the central circadian clock and the light-dark cycle interact to regulate amyloid pathology. Disruption of the central clock in the presence of a light-dark cycle may reduce APP cleavage and plaque formation. These results call into question the proposed simple positive feedback loop between circadian rhythm disruption and Alzheimer\u2019s Disease pathology.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.03.31.645805","type":"posted-content","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T17:21:28Z","timestamp":1743787288000},"source":"Crossref","is-referenced-by-count":1,"title":["Circadian rhythms and the light-dark cycle interact to regulate amyloid plaque accumulation and tau phosphorylation in 5xFAD mice"],"prefix":"10.64898","author":[{"given":"Melvin W.","family":"King","sequence":"first","affiliation":[{"name":"Department of Neurology & Center On Biological Rhythms & Sleep, Washington University School of Medicine in St. Louis, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Jacob","sequence":"additional","affiliation":[{"name":"Department of Neurology & Center On Biological Rhythms & Sleep, Washington University School of Medicine in St. Louis, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashish","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Neurology & Center On Biological Rhythms & Sleep, Washington University School of Medicine in St. Louis, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer H.","family":"Lawrence","sequence":"additional","affiliation":[{"name":"Department of Neurology & Center On Biological Rhythms & Sleep, Washington University School of Medicine in St. Louis, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8873-0360","authenticated-orcid":false,"given":"Erik S.","family":"Musiek","sequence":"additional","affiliation":[{"name":"Department of Neurology & Center On Biological Rhythms & Sleep, Washington University School of Medicine in St. Louis, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041202182886000_2025.03.31.645805v2.1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13809"},{"key":"2026041202182886000_2025.03.31.645805v2.2","doi-asserted-by":"publisher","DOI":"10.4306\/pi.2011.8.4.275"},{"key":"2026041202182886000_2025.03.31.645805v2.3","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awh129"},{"key":"2026041202182886000_2025.03.31.645805v2.4","doi-asserted-by":"publisher","DOI":"10.1126\/science.aah4968"},{"key":"2026041202182886000_2025.03.31.645805v2.5","doi-asserted-by":"publisher","DOI":"10.1016\/0140-6736(92)92817-Y"},{"key":"2026041202182886000_2025.03.31.645805v2.6","doi-asserted-by":"publisher","DOI":"10.1126\/science.add0846"},{"key":"2026041202182886000_2025.03.31.645805v2.7","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1001\/jamaneurol.2017.4719","article-title":"Circadian rest-activity pattern changes in aging and preclinical Alzheimer disease","volume":"75","year":"2018","journal-title":"JAMA Neurol"},{"key":"2026041202182886000_2025.03.31.645805v2.8","doi-asserted-by":"publisher","DOI":"10.1172\/JCI70317"},{"key":"2026041202182886000_2025.03.31.645805v2.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.10.073"},{"key":"2026041202182886000_2025.03.31.645805v2.10","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)00205-1"},{"key":"2026041202182886000_2025.03.31.645805v2.11","doi-asserted-by":"crossref","unstructured":"Yang, G. et al. 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