{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T23:55:25Z","timestamp":1789430125580,"version":"build-2803163510"},"reference-count":76,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,10,31]],"date-time":"2016-10-31T00:00:00Z","timestamp":1477872000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,10,31]],"date-time":"2016-10-31T00:00:00Z","timestamp":1477872000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Alzheimer\u2019s disease (AD) is a circadian clock-related disease. However, it is not very clear whether pre-symptomatic AD leads to circadian disruption or whether malfunction of circadian rhythms exerts influence on development of AD. Here, we report a functional clock that exists in the hippocampus. This oscillator both receives input signals and maintains the cycling of the hippocampal\n                    <jats:italic>Per2<\/jats:italic>\n                    gene. One of the potential inputs to the oscillator is orexin signaling, which can shorten the hippocampal clock period and thereby regulate the expression of clock-controlled-genes (CCGs). A 24-h time course qPCR analysis followed by a JTK_CYCLE algorithm analysis indicated that a number of AD-risk genes are potential CCGs in the hippocampus. Specifically, we found that\n                    <jats:italic>Bace1<\/jats:italic>\n                    and\n                    <jats:italic>Bace2<\/jats:italic>\n                    , which are related to the production of the amyloid-beta peptide, are CCGs.\n                    <jats:italic>BACE1<\/jats:italic>\n                    is inhibited by\n                    <jats:italic>E4BP4<\/jats:italic>\n                    , a repressor of D-box genes, while\n                    <jats:italic>BACE2<\/jats:italic>\n                    is activated by CLOCK:BMAL1. Finally, we observed alterations in the rhythmic expression patterns of\n                    <jats:italic>Bace2<\/jats:italic>\n                    and\n                    <jats:italic>ApoE<\/jats:italic>\n                    in the hippocampus of aged\n                    <jats:italic>APP\/PS1dE9<\/jats:italic>\n                    mice. Our results therefore indicate that there is a circadian oscillator in the hippocampus whose oscillation could be regulated by orexins. Hence, orexin signaling regulates both the hippocampal clock and the circadian oscillation of AD-risk genes.\n                  <\/jats:p>","DOI":"10.1038\/srep36035","type":"journal-article","created":{"date-parts":[[2016,10,31]],"date-time":"2016-10-31T06:48:47Z","timestamp":1477896527000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Orexin signaling regulates both the hippocampal clock and the circadian oscillation of Alzheimer\u2019s disease-risk genes"],"prefix":"10.1038","volume":"6","author":[{"given":"Zhixiong","family":"Ma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiliang","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric Erquan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,10,31]]},"reference":[{"key":"BFsrep36035_CR1","doi-asserted-by":"crossref","first-page":"16219","DOI":"10.1073\/pnas.1408886111","volume":"111","author":"R Zhang","year":"2014","unstructured":"Zhang, R., Lahens, N. 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