{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T15:39:11Z","timestamp":1775057951511,"version":"3.50.1"},"reference-count":52,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T00:00:00Z","timestamp":1730160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lack of sleep, whether acute or chronic, is quite common and negatively affects an individual\u2019s memory and cognitive function. The question of whether chronic sleep deprivation (CSD) causes cognitive impairment to arise and progress is not well studied. To investigate the effects of CSD on memory and cognition, this study began by establishing a CSD mouse model. Behavioral experiments on animals revealed that CSD induced cognitive behavioral abnormalities reminiscent of Alzheimer\u2019s disease. Western blot experiments further demonstrated a considerable increase in amyloid-\u03b2 (A\u03b2) expression in the mouse brain following CSD. Meanwhile, the hub gene Prkcg was searched for in the cerebellum using RNA-seq and bioinformatics analysis. PKC\u03b3 (Prkcg) expression was significantly reduced, as demonstrated by RT-qPCR and Western blot validations. Additionally, CSD was associated with downregulated CREB expression, decreased expression of the endothelin-converting enzyme (ECE1), and increased phosphorylation of ERK1\/2 downstream of PKC\u03b3. These findings suggested that CSD down-regulated PKC\u03b3 expression, decreased ECE1 expression, impaired A\u03b2 degradation, and affected the PKC\u03b3\/ERK\/CREB pathway and the synthesis of memory-related proteins. Overall, this study highlighted how CSD modulated PKC\u03b3-related metabolism, impacting A\u03b2 clearance and the production of memory-related proteins. Such insights are crucial for understanding and preventing sporadic Alzheimer\u2019s disease (sAD) associated with CSD.<\/jats:p>","DOI":"10.3390\/ijms252111634","type":"journal-article","created":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T13:21:39Z","timestamp":1730208099000},"page":"11634","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Chronic Sleep Deprivation Altered the Expression of Memory-Related Genes and Caused Cognitive Memory Dysfunction in Mice"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7325-4837","authenticated-orcid":false,"given":"Xiang","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 211100, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9513-7564","authenticated-orcid":false,"given":"Hanqing","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 211100, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tian","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 211100, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiang","family":"Zhan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 211100, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shu","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 211100, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taijun","family":"Hang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 211100, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 211100, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4483","DOI":"10.1073\/pnas.1721694115","article-title":"\u03b2-Amyloid accumulation in the human brain after one night of sleep deprivation","volume":"115","author":"Wang","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1093\/brain\/awaa443","article-title":"Sleep deprivation impairs molecular clearance from the human brain","volume":"144","author":"Eide","year":"2021","journal-title":"Brain"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1126\/science.1241224","article-title":"Sleep drives metabolite clearance from the adult brain","volume":"342","author":"Xie","year":"2013","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1111\/j.1750-3639.2011.00513.x","article-title":"Widespread tau and amyloid-beta pathology many years after a single traumatic brain injury in humans","volume":"22","author":"Johnson","year":"2011","journal-title":"Brain Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","article-title":"Alzheimer\u2019s disease","volume":"397","author":"Scheltens","year":"2021","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"150ra122","DOI":"10.1126\/scitranslmed.3004291","article-title":"Disruption of the sleep-wake cycle and diurnal fluctuation of amyloid-b in mice with alzheimer\u2019s disease pathology","volume":"4","author":"Roh","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1126\/science.aav2546","article-title":"The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans","volume":"363","author":"Holth","year":"2019","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.neulet.2017.05.054","article-title":"Chronic sleep fragmentation exacerbates amyloid \u03b2 deposition in Alzheimer\u2019s disease model mice","volume":"653","author":"Minakawa","year":"2017","journal-title":"Neurosci. Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.neulet.2014.07.043","article-title":"Chronic sleep restriction elevates brain interleukin-1 beta and tumor necrosis factor-alpha and attenuates brain-derived neurotrophic factor expression","volume":"580","author":"Zielinski","year":"2014","journal-title":"Neurosci. Lett."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e13028","DOI":"10.1111\/bpa.13028","article-title":"Chronic sleep deprivation altered the expression of circadian clock genes and aggravated Alzheimer\u2019s disease neuropathology","volume":"32","author":"Niu","year":"2022","journal-title":"Brain Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.tins.2017.03.001","article-title":"The sleeping cerebellum","volume":"40","author":"Canto","year":"2017","journal-title":"Trends Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Verweij, I.M., Romeijn, N., Smit, D.J., Piantoni, G., Van Someren, E.J., and van der Werf, Y.D. (2014). Sleep deprivation leads to a loss of functional connectivity in frontal brain region. BMC Neurosci., 15.","DOI":"10.1186\/1471-2202-15-88"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2322","DOI":"10.1152\/jn.00339.2011","article-title":"The organization of the human cerebellum estimated by intrinsic functional connectivity","volume":"106","author":"Buckner","year":"2011","journal-title":"J. Neurophysiol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Hoxha, E., Lippiello, P., Zurlo, F., Balbo, I., Santamaria, R., Tempia, F., and Miniaci, M.C. (2018). The emerging role of altered cerebellar synaptic processing in alzheimer\u2019s disease. Front. Aging Neurosci., 10.","DOI":"10.3389\/fnagi.2018.00396"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1093\/brain\/awx194","article-title":"The cerebellum in Alzheimer\u2019s disease: Evaluating its role in cognitive decline","volume":"141","author":"Jacobs","year":"2018","journal-title":"Brain"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1093\/brain\/aww053","article-title":"Cytotoxic T cells go awry in inclusion body myositis","volume":"139","author":"Hohlfeld","year":"2016","journal-title":"Brain"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1007\/BF00230495","article-title":"The distribution of amyloid plaques in the cerebellum and brain stem in Down\u2019s syndrome and Alzheimer\u2019s disease: A light microscopical analysis","volume":"85","author":"Cole","year":"1993","journal-title":"Acta Neuropathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1016\/j.jpsychires.2007.12.002","article-title":"The cerebellum in mild cognitive impairment and Alzheimer\u2019s disease\u2014A structural MRI study","volume":"42","author":"Thomann","year":"2008","journal-title":"J. Psychiatr. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"535816","DOI":"10.4061\/2011\/535816","article-title":"The default mode network in healthy aging and alzheimer\u2019s disease","volume":"2011","author":"Mevel","year":"2011","journal-title":"Int. J. Alzheimers Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1111\/jnc.12728","article-title":"Impairments of long-term depression induction and motor coordination precede A\u03b2 accumulation in the cerebellum of APPswe\/PS1dE9 double transgenic mice","volume":"130","author":"Kuwabara","year":"2014","journal-title":"J. Neurochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/978-1-4939-8994-2_10","article-title":"The Y-maze for assessment of spatial working and reference memory in mice","volume":"1916","author":"Kraeuter","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"ref_22","first-page":"e55718","article-title":"Novel object recognition test for the investigation of learning and memory in mice","volume":"126","author":"Lueptow","year":"2017","journal-title":"J. Vis. Exp."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3659","DOI":"10.1021\/acs.jpcb.2c01769","article-title":"Amyloid beta dodecamer disrupts the neuronal membrane more strongly than the mature fibril: Understanding the role of oligomers in neurotoxicity","volume":"126","author":"Nguyen","year":"2022","journal-title":"J. Phys. Chem. B"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1186\/s13041-021-00835-1","article-title":"Altered hippocampal transcriptome dynamics following sleep deprivation","volume":"14","author":"Gaine","year":"2021","journal-title":"Mol. Brain."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1152\/physiolgenomics.00084.2012","article-title":"Genomic analysis of sleep deprivation reveals translational regulation in the hippocampus","volume":"44","author":"Vecsey","year":"2012","journal-title":"Physiol. Genom."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1038\/sj.mp.4001584","article-title":"Endothelin-converting enzyme-1 is expressed in human cerebral cortex and protects against Alzheimer\u2019s disease","volume":"9","author":"Funalot","year":"2004","journal-title":"Mol. Psychiatry"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8215","DOI":"10.1073\/pnas.0509725103","article-title":"PKC\u03b5 increases endothelin converting enzyme activity and reduces amyloid plaque pathology in transgenic mice","volume":"103","author":"Choi","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1515\/rns.2011.018","article-title":"The role of CREB signaling in Alzheimer\u2019s disease and other cognitive disorders","volume":"22","author":"Saura","year":"2011","journal-title":"Rev. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1038\/npp.2011.107","article-title":"Increasing CREB function in the CA1 region of dorsal hippocampus rescues the spatial memory deficits in a mouse model of Alzheimer\u2019s disease","volume":"36","author":"Yiu","year":"2011","journal-title":"Neuropsychopharmacology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"136","DOI":"10.5607\/en.2012.21.4.136","article-title":"A functional role for creb as a positive regulator of memory formation and LTP","volume":"21","author":"Kida","year":"2012","journal-title":"Exp. Neurobiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1111\/j.1471-4159.2007.04869.x","article-title":"Evidence of Abeta- and transgene-dependent defects in ERK-CREB signaling in Alzheimer\u2019s models","volume":"103","author":"Ma","year":"2007","journal-title":"J. Neurochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"118020","DOI":"10.1016\/j.lfs.2020.118020","article-title":"The role of CREB and BDNF in neurobiology and treatment of Alzheimer\u2019s disease","volume":"257","author":"Amidfar","year":"2020","journal-title":"Life Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e13333","DOI":"10.1111\/acel.13333","article-title":"Activation of CREB-mediated autophagy by thioperamide ameliorates beta-amyloid pathology and cognition in Alzheimer\u2019s disease","volume":"20","author":"Wang","year":"2021","journal-title":"Aging Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.jalz.2014.04.514","article-title":"At the interface of sensory and motor dysfunctions and Alzheimer\u2019s disease","volume":"11","author":"Albers","year":"2015","journal-title":"Alzh. Dement."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1111\/j.1750-3639.2010.00469.x","article-title":"Deposition of hyperphosphorylated tau in cerebellum of PS1 E280A Alzheimer\u2019s disease","volume":"21","author":"Matschke","year":"2011","journal-title":"Brain Pathol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Chai, Y., Fang, Z., Yang, F.N., Xu, S., Deng, Y., Raine, A., Wang, J., Yu, M., Basner, M., and Goel, N. (2020). Two nights of recovery sleep restores hippocampal connectivity but not episodic memory after total sleep deprivation. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-65086-x"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1016\/j.neurobiolaging.2014.02.011","article-title":"Sleep deprivation impairs memory, tau metabolism, and synaptic integrity of a mouse model of Alzheimer\u2019s disease with plaques and tangles","volume":"35","author":"Joshi","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Uryash, A., Flores, V., Adams, J.A., Allen, P.D., and Lopez, J.R. (2020). Memory and learning deficits are associated with Ca2+ dyshomeostasis in normal aging. Front. Aging Neurosci., 12.","DOI":"10.3389\/fnagi.2020.00224"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/j.neuron.2007.06.001","article-title":"The role of the GluR2 subunit in AMPA receptor function and synaptic plasticity","volume":"54","author":"Isaac","year":"2007","journal-title":"Neuron"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1007\/s12035-020-02135-6","article-title":"Protein kinase C-gamma knockout mice show impaired hippocampal short-term memory while preserved long-term memory","volume":"58","author":"Cox","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.phrs.2007.04.013","article-title":"The aging brain, a key target for the future: The protein kinase C involvement","volume":"55","author":"Pascale","year":"2007","journal-title":"Pharmacol. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1093\/oxfordjournals.jbchem.a003274","article-title":"Protein kinase C\u03b3 (PKC\u03b3): Function of neuron specific isotype","volume":"132","author":"Saito","year":"2002","journal-title":"J. Biochem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.neuroscience.2019.06.030","article-title":"Hippocampal protein kinase c gamma signaling mediates the impairment of spatial learning and memory in prenatally stressed offspring rats","volume":"414","author":"Su","year":"2019","journal-title":"Neuroscience"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1523\/JNEUROSCI.08-02-00369.1988","article-title":"Distribution of protein kinase C-like immunoreactive neurons in rat brain","volume":"8","author":"Saito","year":"1988","journal-title":"J. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/361031a0","article-title":"A synaptic model of memory: Long-term potentiation in the hippocampus","volume":"361","author":"Bliss","year":"1993","journal-title":"Nature"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.neulet.2009.04.064","article-title":"Deficits in ERK and CREB activation in the hippocampus after traumatic brain injury","volume":"459","author":"Atkins","year":"2009","journal-title":"Neurosci. Lett."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"30956","DOI":"10.18632\/oncotarget.16042","article-title":"Long-term neurocognitive dysfunction in offspring via NGF\/ERK\/CREB signaling pathway caused by ketamine exposure during the second trimester of pregnancy in rats","volume":"8","author":"Li","year":"2017","journal-title":"Oncotarget"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.1016\/j.yexcr.2012.04.015","article-title":"OX2R activation induces PKC-mediated ERK and CREB phosphorylation","volume":"318","author":"Guo","year":"2012","journal-title":"Exp. Cell. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2531","DOI":"10.1038\/nprot.2013.155","article-title":"Object recognition test in mice","volume":"8","author":"Leger","year":"2013","journal-title":"Nat. Protoc."},{"key":"ref_50","first-page":"e52434","article-title":"Use of the open field maze to measure locomotor and anxiety-like behavior in mice","volume":"96","author":"Seibenhener","year":"2015","journal-title":"J. Vis. Exp."},{"key":"ref_51","first-page":"e1088","article-title":"Elevated plus maze for mice","volume":"22","author":"Komada","year":"2008","journal-title":"J. Vis. Exp."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/nmeth.f.315","article-title":"RNAzol\u00ae RT: A new single-step method for isolation of RNA","volume":"7","author":"Chomczynski","year":"2010","journal-title":"Nat. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/21\/11634\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:23:34Z","timestamp":1760113414000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/21\/11634"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,29]]},"references-count":52,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["ijms252111634"],"URL":"https:\/\/doi.org\/10.3390\/ijms252111634","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,29]]}}}