{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T17:09:04Z","timestamp":1779124144999,"version":"3.51.4"},"reference-count":66,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T00:00:00Z","timestamp":1763596800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T00:00:00Z","timestamp":1763596800000},"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":["EMBO Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The \u03b2-secretase BACE1 has become a prime target in Alzheimer\u2019s disease (AD) therapy, because it drives the production of pathogenic amyloid \u03b2 peptides. However, clinical trials with BACE1-targeting drugs were halted due to adverse effects on cognitive performance. We propose here that cognitive impairment by BACE1 inhibitors may be a corollary of a higher function of BACE1 related to proper sleep regulation. To address non-enzymatic effects of BACE1 on ion channels likely involved in the sleep-wake cycle, we analyze sleep patterns in both BACE1-KO mice and a newly generated transgenic line expressing a proteolysis-deficient BACE1 variant (BACE1-KI). We find that BACE1-KI and BACE1-KO mice display common and distinct sleep-wake disturbances. Compared with their respective wild-type littermates, both mutant lines sleep less during the light phase (when they preferentially rest). Furthermore, transition rates between wake and sleep states are altered, as are sleep spindles and EEG power spectra mainly in the gamma range. Thus, a better understanding of how BACE1 interferes with sleep-modulated behaviors is needed if clinical trials with BACE1-targeted inhibitors are to resume.<\/jats:p>","DOI":"10.1038\/s44319-025-00604-4","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T14:29:58Z","timestamp":1763648998000},"page":"50-68","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["BACE1 regulates sleep\u2013wake cycle through both enzymatic and non\u2013enzymatic actions"],"prefix":"10.1038","volume":"27","author":[{"given":"Hannah","family":"Heininger","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0968-6405","authenticated-orcid":false,"given":"Xiao","family":"Feng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alp","family":"Altunkaya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5699-8063","authenticated-orcid":false,"given":"Fang","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9101-7491","authenticated-orcid":false,"given":"Florian","family":"Stockinger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benedikt","family":"Wefers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3414-307X","authenticated-orcid":false,"given":"Stephan A","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7461-8602","authenticated-orcid":false,"given":"Pieter","family":"Giesbertz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4972-9811","authenticated-orcid":false,"given":"Sarah K","family":"Tschirner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5047-4410","authenticated-orcid":false,"given":"Dorina","family":"Shqau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helmuth","family":"Adelsberger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexey","family":"Ponomarenko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0132-9591","authenticated-orcid":false,"given":"Thomas","family":"Fenzl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Alzheimer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2211-2575","authenticated-orcid":false,"given":"Stefan F","family":"Lichtenthaler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6414-8923","authenticated-orcid":false,"given":"Tobias","family":"Huth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,11,20]]},"reference":[{"key":"604_CR1","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1016\/j.yjmcc.2015.10.006","volume":"89","author":"M Agsten","year":"2015","unstructured":"Agsten M, Hessler S, Lehnert S, Volk T, Rittger A, Hartmann S, Raab C, Kim DY, Groemer TW, Schwake M et al (2015) BACE1 modulates gating of KCNQ1 (Kv7.1) and cardiac delayed rectifier KCNQ1\/KCNE1 (IKs). J Mol Cell Cardiol 89:335\u2013348","journal-title":"J Mol Cell Cardiol"},{"key":"604_CR2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-51560-3","volume":"14","author":"A Altunkaya","year":"2024","unstructured":"Altunkaya A, Deichsel C, Kreuzer M, Nguyen D-M, Wintergerst A-M, Rammes G, Schneider G, Fenzl T (2024) Altered sleep behavior strengthens face validity in the ArcA\u03b2 mouse model for Alzheimer\u2019s disease. Sci Rep 14:951","journal-title":"Sci Rep"},{"key":"604_CR3","doi-asserted-by":"publisher","first-page":"707789","DOI":"10.3389\/fncel.2021.707789","volume":"15","author":"T Bayasgalan","year":"2021","unstructured":"Bayasgalan T, Stupniki S, Kov\u00e1cs A, Csemer A, Szentesi P, Pocsai K, Dionisio L, Spitzmaul G, P\u00e1l B (2021) Alteration of mesopontine cholinergic function by the lack of KCNQ4 subunit. Front Cell Neurosci 15:707789","journal-title":"Front Cell Neurosci"},{"key":"604_CR4","doi-asserted-by":"publisher","first-page":"pe24","DOI":"10.1126\/scisignal.2004296","volume":"6","author":"I Bezprozvanny","year":"2013","unstructured":"Bezprozvanny I (2013) Presenilins and calcium signaling-systems biology to the rescue. Sci Signal 6:pe24","journal-title":"Sci Signal"},{"key":"604_CR5","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.1016\/j.neuron.2025.01.030","volume":"113","author":"D Bi","year":"2025","unstructured":"Bi D, Bao H, Yang X, Wu Z, Yang X, Xu G, Liu X, Wan Z, Liu J, He J et al (2025) BACE1-dependent cleavage of GABAA receptor contributes to neural hyperexcitability and disease progression in Alzheimer\u2019s disease. Neuron 113:1051\u20131064.e6","journal-title":"Neuron"},{"key":"604_CR6","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1038\/85064","volume":"4","author":"H Cai","year":"2001","unstructured":"Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL, Wong PC (2001) BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat Neurosci 4:233\u2013234","journal-title":"Nat Neurosci"},{"key":"604_CR7","doi-asserted-by":"publisher","first-page":"12323","DOI":"10.1073\/pnas.1001745107","volume":"107","author":"X Chen","year":"2010","unstructured":"Chen X, Kovalchuk Y, Adelsberger H, Henning HA, Sausbier M, Wietzorrek G, Ruth P, Yarom Y, Konnerth A (2010) Disruption of the olivo-cerebellar circuit by Purkinje neuron-specific ablation of BK channels. Proc Natl Acad Sci USA 107:12323\u201312328","journal-title":"Proc Natl Acad Sci USA"},{"key":"604_CR8","doi-asserted-by":"publisher","first-page":"2015","DOI":"10.1038\/emboj.2013.146","volume":"32","author":"C Cheret","year":"2013","unstructured":"Cheret C, Willem M, Fricker FR, Wende H, Wulf-Goldenberg A, Tahirovic S, Nave K-A, Saftig P, Haass C, Garratt AN et al (2013) Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles. EMBO J 32:2015\u20132028","journal-title":"EMBO J"},{"key":"604_CR9","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.nbd.2012.08.011","volume":"49","author":"A Colombo","year":"2013","unstructured":"Colombo A, Wang H, Kuhn P-H, Page R, Kremmer E, Dempsey PJ, Crawford HC, Lichtenthaler SF (2013) Constitutive \u03b1- and \u03b2-secretase cleavages of the amyloid precursor protein are partially coupled in neurons, but not in frequently used cell lines. Neurobiol Dis 49:137\u2013147","journal-title":"Neurobiol Dis"},{"key":"604_CR10","doi-asserted-by":"publisher","first-page":"W242","DOI":"10.1093\/nar\/gky354","volume":"46","author":"J-P Concordet","year":"2018","unstructured":"Concordet J-P, Haeussler M (2018) CRISPOR: intuitive guide selection for CRISPR\/Cas9 genome editing experiments and screens. Nucleic Acids Res 46:W242\u2013W245","journal-title":"Nucleic Acids Res"},{"key":"604_CR11","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/s41592-019-0638-x","volume":"17","author":"V Demichev","year":"2020","unstructured":"Demichev V, Messner CB, Vernardis SI, Lilley KS, Ralser M (2020) DIA-NN: neural networks and interference correction enable deep proteome coverage in high throughput. Nat Methods 17:41\u201344","journal-title":"Nat Methods"},{"key":"604_CR12","doi-asserted-by":"publisher","first-page":"9013","DOI":"10.1523\/JNEUROSCI.0028-19.2019","volume":"39","author":"M Dierich","year":"2019","unstructured":"Dierich M, Hartmann S, Dietrich N, Moeser P, Brede F, Johnson Chacko L, Tziridis K, Schilling A, Krauss P, Hessler S et al (2019) \u03b2-Secretase BACE1 Is required for normal cochlear function. J Neurosci 39:9013\u20139027","journal-title":"J Neurosci"},{"key":"604_CR13","doi-asserted-by":"publisher","first-page":"2550","DOI":"10.1074\/mcp.M114.041533","volume":"14","author":"B Dislich","year":"2015","unstructured":"Dislich B, Wohlrab F, Bachhuber T, M\u00fcller SA, Kuhn P-H, Hogl S, Meyer-Luehmann M, Lichtenthaler SF (2015) Label-free quantitative proteomics of mouse cerebrospinal fluid detects \u03b2-site APP cleaving enzyme (BACE1) protease substrates in vivo. Mol Cell Proteom 14:2550\u20132563","journal-title":"Mol Cell Proteom"},{"key":"604_CR14","doi-asserted-by":"publisher","first-page":"30797","DOI":"10.1074\/jbc.M505249200","volume":"280","author":"D Dominguez","year":"2005","unstructured":"Dominguez D, Tournoy J, Hartmann D, Huth T, Cryns K, Deforce S, Serneels L, Camacho IE, Marjaux E, Craessaerts K et al (2005) Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice. J Biol Chem 280:30797\u201330806","journal-title":"J Biol Chem"},{"key":"604_CR15","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1186\/s13195-019-0520-1","volume":"11","author":"MF Egan","year":"2019","unstructured":"Egan MF, Mukai Y, Voss T, Kost J, Stone J, Furtek C, Mahoney E, Cummings JL, Tariot PN, Aisen PS et al (2019) Further analyses of the safety of verubecestat in the phase 3 EPOCH trial of mild-to-moderate Alzheimer\u2019s disease. Alzheimers Res Ther 11:68","journal-title":"Alzheimers Res Ther"},{"key":"604_CR16","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/j.jneumeth.2007.07.007","volume":"166","author":"T Fenzl","year":"2007","unstructured":"Fenzl T, Romanowski CPN, Flachskamm C, Honsberg K, Boll E, Hoehne A, Kimura M (2007) Fully automated sleep deprivation in mice as a tool in sleep research. J Neurosci Methods 166:229\u2013235","journal-title":"J Neurosci Methods"},{"key":"604_CR17","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2202-12-29","volume":"12","author":"T Fenzl","year":"2011","unstructured":"Fenzl T, Touma C, Romanowski CP, Ruschel J, Holsboer F, Landgraf R, Kimura M, Yassouridis A (2011) Sleep disturbances in highly stress reactive mice: modeling endophenotypes of major depression. BMC Neurosci 12:29","journal-title":"BMC Neurosci"},{"key":"604_CR18","doi-asserted-by":"publisher","first-page":"10337","DOI":"10.1523\/JNEUROSCI.2160-16.2016","volume":"36","author":"MS Fleming","year":"2016","unstructured":"Fleming MS, Li JJ, Ramos D, Li T, Talmage DA, Abe S-I, Arber S, Luo W (2016) A RET-ER81-NRG1 signaling pathway drives the development of Pacinian corpuscles. J Neurosci 36:10337\u201310355","journal-title":"J Neurosci"},{"key":"604_CR19","doi-asserted-by":"publisher","first-page":"3480","DOI":"10.1523\/JNEUROSCI.2643-17.2018","volume":"38","author":"S Hartmann","year":"2018","unstructured":"Hartmann S, Zheng F, Kyncl MC, Karch S, Voelkl K, Zott B, D\u2019Avanzo C, Lomoio S, Tesco G, Kim DY et al (2018) \u03b2-Secretase BACE1 promotes surface expression and function of Kv3.4 at hippocampal mossy fiber synapses. J Neurosci 38:3480\u20133494","journal-title":"J Neurosci"},{"key":"604_CR20","doi-asserted-by":"publisher","first-page":"e8477","DOI":"10.1371\/journal.pone.0008477","volume":"4","author":"ML Hemming","year":"2009","unstructured":"Hemming ML, Elias JE, Gygi SP, Selkoe DJ (2009) Identification of beta-secretase (BACE1) substrates using quantitative proteomics. PLoS ONE 4:e8477","journal-title":"PLoS ONE"},{"key":"604_CR21","doi-asserted-by":"publisher","first-page":"3298","DOI":"10.1523\/JNEUROSCI.3127-14.2015","volume":"35","author":"S Hessler","year":"2015","unstructured":"Hessler S, Zheng F, Hartmann S, Rittger A, Lehnert S, V\u00f6lkel M, Nissen M, Edelmann E, Saftig P, Schwake M et al (2015) \u03b2-Secretase BACE1 regulates hippocampal and reconstituted M-currents in a \u03b2-subunit-like fashion. J Neurosci 35:3298\u20133311","journal-title":"J Neurosci"},{"key":"604_CR22","doi-asserted-by":"publisher","first-page":"38408","DOI":"10.1074\/jbc.M112.415505","volume":"287","author":"B Hitt","year":"2012","unstructured":"Hitt B, Riordan SM, Kukreja L, Eimer WA, Rajapaksha TW, Vassar R (2012) \u03b2-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1)-deficient mice exhibit a close homolog of L1 (CHL1) loss-of-function phenotype involving axon guidance defects. J Biol Chem 287:38408\u201338425","journal-title":"J Biol Chem"},{"key":"604_CR23","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/1750-1326-5-31","volume":"5","author":"BD Hitt","year":"2010","unstructured":"Hitt BD, Jaramillo TC, Chetkovich DM, Vassar R (2010) BACE1-\/- mice exhibit seizure activity that does not correlate with sodium channel level or axonal localization. Mol Neurodegener 5:31","journal-title":"Mol Neurodegener"},{"key":"604_CR24","doi-asserted-by":"publisher","first-page":"1520","DOI":"10.1038\/nn1797","volume":"9","author":"X Hu","year":"2006","unstructured":"Hu X, Hicks CW, He W, Wong P, Macklin WB, Trapp BD, Yan R (2006) Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci 9:1520\u20131525","journal-title":"Nat Neurosci"},{"key":"604_CR25","doi-asserted-by":"publisher","first-page":"8819","DOI":"10.1523\/JNEUROSCI.1334-10.2010","volume":"30","author":"X Hu","year":"2010","unstructured":"Hu X, Zhou X, He W, Yang J, Xiong W, Wong P, Wilson CG, Yan R (2010) BACE1 deficiency causes altered neuronal activity and neurodegeneration. J Neurosci 30:8819\u20138829","journal-title":"J Neurosci"},{"key":"604_CR26","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/s41596-018-0082-x","volume":"14","author":"CS Hughes","year":"2019","unstructured":"Hughes CS, Moggridge S, M\u00fcller T, Sorensen PH, Morin GB, Krijgsveld J (2019) Single-pot, solid-phase-enhanced sample preparation for proteomics experiments. Nat Protoc 14:68\u201385","journal-title":"Nat Protoc"},{"key":"604_CR27","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1006\/mcne.1999.0811","volume":"14","author":"I Hussain","year":"1999","unstructured":"Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, Gloger IS, Murphy KE, Southan CD, Ryan DM et al (1999) Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol Cell Neurosci 14:419\u2013427","journal-title":"Mol Cell Neurosci"},{"key":"604_CR28","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1016\/j.nbd.2008.10.015","volume":"33","author":"T Huth","year":"2009","unstructured":"Huth T, Schmidt-Neuenfeldt K, Rittger A, Saftig P, Reiss K, Alzheimer C (2009) Non-proteolytic effect of \u00df-site APP-cleaving enzyme 1 (BACE1) on sodium channel function. Neurobiol Dis 33:282\u2013289","journal-title":"Neurobiol Dis"},{"key":"604_CR29","doi-asserted-by":"publisher","first-page":"W459","DOI":"10.1093\/nar\/gkt436","volume":"41","author":"DN Ivankov","year":"2013","unstructured":"Ivankov DN, Bogatyreva NS, H\u00f6nigschmid P, Dislich B, Hogl S, Kuhn P-H, Frishman D, Lichtenthaler SF (2013) QARIP: a web server for quantitative proteomic analysis of regulated intramembrane proteolysis. Nucleic Acids Res 41:W459\u2013W464","journal-title":"Nucleic Acids Res"},{"key":"604_CR30","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-64975-9","volume":"14","author":"L Joyce","year":"2024","unstructured":"Joyce L, Carrillo Mas C, Meedt V, Kreuzer M, Schneider G, Fenzl T (2024) Isoflurane anesthesia and sleep deprivation trigger delayed and selective sleep alterations. Sci Rep 14:14060","journal-title":"Sci Rep"},{"key":"604_CR31","doi-asserted-by":"publisher","first-page":"441","DOI":"10.2174\/1567205011666140604122059","volume":"11","author":"PC Kandalepas","year":"2014","unstructured":"Kandalepas PC, Vassar R (2014) The normal and pathologic roles of the Alzheimer\u2019s \u03b2-secretase, BACE1. Curr Alzheimer Res 11:441\u2013449","journal-title":"Curr Alzheimer Res"},{"key":"604_CR32","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1038\/ncb1602","volume":"9","author":"DY Kim","year":"2007","unstructured":"Kim DY, Carey BW, Wang H, Ingano LAM, Binshtok AM, Wertz MH, Pettingell WH, He P, Lee VM-Y, Woolf CJ et al (2007) BACE1 regulates voltage-gated sodium channels and neuronal activity. Nat Cell Biol 9:755\u2013764","journal-title":"Nat Cell Biol"},{"key":"604_CR33","doi-asserted-by":"publisher","first-page":"778022","DOI":"10.3389\/fncir.2021.778022","volume":"15","author":"A Klemz","year":"2021","unstructured":"Klemz A, Wildner F, T\u00fct\u00fcnc\u00fc E, Gerevich Z (2021) Regulation of hippocampal gamma oscillations by modulation of intrinsic neuronal excitability. Front Neural Circuits 15:778022","journal-title":"Front Neural Circuits"},{"key":"604_CR34","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1016\/j.mex.2015.04.005","volume":"2","author":"M Kreuzer","year":"2015","unstructured":"Kreuzer M, Polta S, Gapp J, Schuler C, Kochs EF, Fenzl T (2015) Sleep scoring made easy-Semi-automated sleep analysis software and manual rescoring tools for basic sleep research in mice. MethodsX 2:232\u2013240","journal-title":"MethodsX"},{"key":"604_CR35","doi-asserted-by":"publisher","first-page":"3157","DOI":"10.1038\/emboj.2012.173","volume":"31","author":"P-H Kuhn","year":"2012","unstructured":"Kuhn P-H, Koroniak K, Hogl S, Colombo A, Zeitschel U, Willem M, Volbracht C, Schepers U, Imhof A, Hoffmeister A et al (2012) Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons. EMBO J 31:3157\u20133168","journal-title":"EMBO J"},{"key":"604_CR36","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1080\/19336950.2016.1196307","volume":"10","author":"S Lehnert","year":"2016","unstructured":"Lehnert S, Hartmann S, Hessler S, Adelsberger H, Huth T, Alzheimer C (2016) Ion channel regulation by \u03b2-secretase BACE1 - enzymatic and non-enzymatic effects beyond Alzheimer\u2019s disease. Channels 10:365\u2013378","journal-title":"Channels"},{"key":"604_CR37","doi-asserted-by":"publisher","DOI":"10.1126\/science.abh3021","volume":"375","author":"S-B Li","year":"2022","unstructured":"Li S-B, Damonte VM, Chen C, Wang GX, Kebschull JM, Yamaguchi H, Bian W-J, Purmann C, Pattni R, Urban AE et al (2022) Hyperexcitable arousal circuits drive sleep instability during aging. Science 375:eabh3021","journal-title":"Science"},{"key":"604_CR38","doi-asserted-by":"publisher","first-page":"1456","DOI":"10.1073\/pnas.97.4.1456","volume":"97","author":"X Lin","year":"2000","unstructured":"Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J (2000) Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci USA 97:1456\u20131460","journal-title":"Proc Natl Acad Sci USA"},{"key":"604_CR39","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1038\/85059","volume":"4","author":"Y Luo","year":"2001","unstructured":"Luo Y, Bolon B, Kahn S, Bennett BD, Babu-Khan S, Denis P, Fan W, Kha H, Zhang J, Gong Y et al (2001) Mice deficient in BACE1, the Alzheimer\u2019s beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat Neurosci 4:231\u2013232","journal-title":"Nat Neurosci"},{"key":"604_CR40","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.525970","volume":"14","author":"BA Mander","year":"2020","unstructured":"Mander BA (2020) Local sleep and Alzheimer\u2019s disease pathophysiology. Front Neurosci 14:525970","journal-title":"Front Neurosci"},{"key":"604_CR41","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/nm.3508","volume":"20","author":"DJ Marchant","year":"2014","unstructured":"Marchant DJ, Bellac CL, Moraes TJ, Wadsworth SJ, Dufour A, Butler GS, Bilawchuk LM, Hendry RG, Robertson AG, Cheung CT et al (2014) A new transcriptional role for matrix metalloproteinase-12 in antiviral immunity. Nat Med 20:493\u2013502","journal-title":"Nat Med"},{"key":"604_CR42","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1038\/s41582-021-00545-1","volume":"17","author":"E McDade","year":"2021","unstructured":"McDade E, Voytyuk I, Aisen P, Bateman RJ, Carrillo MC, De Strooper B, Haass C, Reiman EM, Sperling R, Tariot PN et al (2021) The case for low-level BACE1 inhibition for the prevention of Alzheimer disease. Nat Rev Neurol 17:703\u2013714","journal-title":"Nat Rev Neurol"},{"key":"604_CR43","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/s13024-023-00596-6","volume":"18","author":"SA M\u00fcller","year":"2023","unstructured":"M\u00fcller SA, Shmueli MD, Feng X, T\u00fcshaus J, Schumacher N, Clark R, Smith BE, Chi A, Rose-John S, Kennedy ME et al (2023) The Alzheimer\u2019s disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130. Mol Neurodegener 18:13","journal-title":"Mol Neurodegener"},{"key":"604_CR44","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1080\/14740338.2025.2467811","volume":"24","author":"A Naidu","year":"2025","unstructured":"Naidu A, Silverglate B, Silverglate M, Grossberg GT (2025) Safety concerns associated with BACE1 inhibitors - past, present and future. Expert Opin Drug Saf 24:767\u2013772","journal-title":"Expert Opin Drug Saf"},{"key":"604_CR45","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aao5620","volume":"10","author":"M-H Ou-Yang","year":"2018","unstructured":"Ou-Yang M-H, Kurz JE, Nomura T, Popovic J, Rajapaksha TW, Dong H, Contractor A, Chetkovich DM, Tourtellotte WG, Vassar R (2018) Axonal organization defects in the hippocampus of adult conditional BACE1 knockout mice. Sci Transl Med 10:eaao5620","journal-title":"Sci Transl Med"},{"key":"604_CR46","doi-asserted-by":"publisher","first-page":"D543","DOI":"10.1093\/nar\/gkae1011","volume":"53","author":"Y Perez-Riverol","year":"2025","unstructured":"Perez-Riverol Y, Bandla C, Kundu DJ, Kamatchinathan S, Bai J, Hewapathirana S, John NS, Prakash A, Walzer M, Wang S et al (2025) The PRIDE database at 20 years: 2025 update. Nucleic Acids Res 53:D543\u2013D553","journal-title":"Nucleic Acids Res"},{"key":"604_CR47","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13024-016-0134-z","volume":"11","author":"M Pigoni","year":"2016","unstructured":"Pigoni M, Wanngren J, Kuhn P-HH, Munro KM, Gunnersen JM, Takeshima H, Feederle R, Voytyuk I, De Strooper B, Levasseur MD et al (2016) Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons. Mol Neurodegener 11:1\u201318","journal-title":"Mol Neurodegener"},{"key":"604_CR48","doi-asserted-by":"publisher","first-page":"60","DOI":"10.3389\/fnbeh.2013.00060","volume":"7","author":"SA Polta","year":"2013","unstructured":"Polta SA, Fenzl T, Jakubcakova V, Kimura M, Yassouridis A, Wotjak CT (2013) Prognostic and symptomatic aspects of rapid eye movement sleep in a mouse model of posttraumatic stress disorder. Front Behav Neurosci 7:60","journal-title":"Front Behav Neurosci"},{"key":"604_CR49","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.tics.2014.12.002","volume":"19","author":"S Ray","year":"2015","unstructured":"Ray S, Maunsell JHR (2015) Do gamma oscillations play a role in cerebral cortex?. Trends Cogn Sci 19:78\u201385","journal-title":"Trends Cogn Sci"},{"key":"604_CR50","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1093\/sleep\/33.4.427","volume":"33","author":"CPN Romanowski","year":"2010","unstructured":"Romanowski CPN, Fenzl T, Flachskamm C, Wurst W, Holsboer F, Deussing JM, Kimura M (2010) Central deficiency of corticotropin-releasing hormone receptor type 1 (CRH-R1) abolishes effects of CRH on NREM but not on REM sleep in mice. Sleep 33:427\u2013436","journal-title":"Sleep"},{"key":"604_CR51","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1038\/990114","volume":"402","author":"S Sinha","year":"1999","unstructured":"Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF, Frigon N, Hong J et al (1999) Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 402:537\u2013540","journal-title":"Nature"},{"key":"604_CR52","doi-asserted-by":"publisher","first-page":"10536","DOI":"10.1074\/jbc.M112.444703","volume":"288","author":"I St\u00fctzer","year":"2013","unstructured":"St\u00fctzer I, Selevsek N, Esterh\u00e1zy D, Schmidt A, Aebersold R, Stoffel M (2013) Systematic proteomic analysis identifies \u03b2-site amyloid precursor protein cleaving enzyme 2 and 1 (BACE2 and BACE1) substrates in pancreatic \u03b2-cells. J Biol Chem 288:10536\u201310547","journal-title":"J Biol Chem"},{"key":"604_CR53","doi-asserted-by":"publisher","first-page":"e4325","DOI":"10.1371\/journal.pone.0004325","volume":"4","author":"C Touma","year":"2009","unstructured":"Touma C, Fenzl T, Ruschel J, Palme R, Holsboer F, Kimura M, Landgraf R (2009) Rhythmicity in mice selected for extremes in stress reactivity: behavioural, endocrine and sleep changes resembling endophenotypes of major depression. PLoS ONE 4:e4325","journal-title":"PLoS ONE"},{"key":"604_CR54","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2020105693","volume":"39","author":"J T\u00fcshaus","year":"2020","unstructured":"T\u00fcshaus J, M\u00fcller SA, Kataka ES, Zaucha J, Sebastian Monasor L, Su M, G\u00fcner G, Jocher G, Tahirovic S, Frishman D et al (2020) An optimized quantitative proteomics method establishes the cell type-resolved mouse brain secretome. EMBO J 39:e105693","journal-title":"EMBO J"},{"key":"604_CR55","doi-asserted-by":"publisher","first-page":"5116","DOI":"10.1073\/pnas.091062498","volume":"98","author":"VG Tusher","year":"2001","unstructured":"Tusher VG, Tibshirani R, Chu G (2001) Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 98:5116\u20135121","journal-title":"Proc Natl Acad Sci USA"},{"key":"604_CR56","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1038\/nmeth.3901","volume":"13","author":"S Tyanova","year":"2016","unstructured":"Tyanova S, Temu T, Sinitcyn P, Carlson A, Hein MY, Geiger T, Mann M, Cox J (2016) The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat Methods 13:731\u2013740","journal-title":"Nat Methods"},{"key":"604_CR57","doi-asserted-by":"publisher","first-page":"zsy218","DOI":"10.1093\/sleep\/zsy218","volume":"42","author":"DS Uygun","year":"2019","unstructured":"Uygun DS, Katsuki F, Bolortuya Y, Aguilar DD, McKenna JT, Thankachan S, McCarley RW, Basheer R, Brown RE, Strecker RE et al (2019) Validation of an automated sleep spindle detection method for mouse electroencephalography. Sleep 42:zsy218","journal-title":"Sleep"},{"key":"604_CR58","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1126\/science.286.5440.735","volume":"286","author":"R Vassar","year":"1999","unstructured":"Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R et al (1999) Beta-secretase cleavage of Alzheimer\u2019s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735\u2013741","journal-title":"Science"},{"key":"604_CR59","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1016\/j.cell.2012.02.046","volume":"149","author":"L Verret","year":"2012","unstructured":"Verret L, Mann EO, Hang GB, Barth AMI, Cobos I, Ho K, Devidze N, Masliah E, Kreitzer AC, Mody I et al (2012) Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in alzheimer model. Cell 149:708\u2013721","journal-title":"Cell"},{"key":"604_CR60","doi-asserted-by":"publisher","first-page":"e201800026","DOI":"10.26508\/lsa.201800026","volume":"1","author":"I Voytyuk","year":"2018","unstructured":"Voytyuk I, Mueller SA, Herber J, Snellinx A, Moechars D, van Loo G, Lichtenthaler SF, De Strooper B (2018) BACE2 distribution in major brain cell types and identification of novel substrates. Life Sci Alliance 1:e201800026","journal-title":"Life Sci Alliance"},{"key":"604_CR61","doi-asserted-by":"publisher","DOI":"10.1038\/srep44249","volume":"7","author":"M Weber","year":"2017","unstructured":"Weber M, Wu T, Meilandt WJ, Dominguez SL, Solanoy HO, Maloney JA, Ngu H, Baca M, Kung C, Lima L et al (2017) BACE1 across species: a comparison of the in vivo consequences of BACE1 deletion in mice and rats. Sci Rep 7:44249","journal-title":"Sci Rep"},{"key":"604_CR62","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1007\/978-1-0716-2990-1_8","volume":"2631","author":"B Wefers","year":"2023","unstructured":"Wefers B, Wurst W, K\u00fchn R (2023) Gene editing in mouse zygotes using the CRISPR\/Cas9 system. Methods Mol Biol 2631:207\u2013230","journal-title":"Methods Mol Biol"},{"key":"604_CR63","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1126\/science.1132341","volume":"314","author":"M Willem","year":"2006","unstructured":"Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, DeStrooper B, Saftig P, Birchmeier C, Haass C (2006) Control of peripheral nerve myelination by the beta-secretase BACE1. Science 314:664\u2013666","journal-title":"Science"},{"key":"604_CR64","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1038\/990107","volume":"402","author":"R Yan","year":"1999","unstructured":"Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WR, Buhl AE et al (1999) Membrane-anchored aspartyl protease with Alzheimer\u2019s disease beta-secretase activity. Nature 402:533\u2013537","journal-title":"Nature"},{"key":"604_CR65","doi-asserted-by":"publisher","first-page":"6197","DOI":"10.1523\/JNEUROSCI.2124-22.2023","volume":"43","author":"AY Yao","year":"2023","unstructured":"Yao AY, Halloran PJ, Ge Y, Singh N, Zhou J, Galske J, He W, Yan R, Hu X (2023) Bace1 deletion in the adult reverses epileptiform activity and sleep-wake disturbances in AD mice. J Neurosci 43:6197\u20136211. JN-RM-2124-22","journal-title":"J Neurosci"},{"key":"604_CR66","doi-asserted-by":"publisher","first-page":"25927","DOI":"10.1074\/jbc.M112.377465","volume":"287","author":"L Zhou","year":"2012","unstructured":"Zhou L, Bar\u00e3o S, Laga M, Bockstael K, Borgers M, Gijsen H, Annaert W, Moechars D, Mercken M, Gevaert K et al (2012) The neural cell adhesion molecules L1 and CHL1 are cleaved by BACE1 protease in vivo. J Biol Chem 287:25927\u201325940","journal-title":"J Biol Chem"}],"container-title":["EMBO Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1038\/s44319-025-00604-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1038\/s44319-025-00604-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1038\/s44319-025-00604-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T16:37:28Z","timestamp":1779122248000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1038\/s44319-025-00604-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,20]]},"references-count":66,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1,12]]}},"alternative-id":["604"],"URL":"https:\/\/doi.org\/10.1038\/s44319-025-00604-4","relation":{},"ISSN":["1469-3178"],"issn-type":[{"value":"1469-3178","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,20]]},"assertion":[{"value":"25 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 September 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 October 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 November 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclosure and competing interests statement"}}]}}