{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:45:03Z","timestamp":1785422703832,"version":"3.56.0"},"reference-count":75,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T00:00:00Z","timestamp":1775088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["ZIAHD008755"],"award-info":[{"award-number":["ZIAHD008755"]}]},{"award":["ZIAHD008755"],"award-info":[{"award-number":["ZIAHD008755"]}],"id":[{"id":"https:\/\/ror.org\/04byxyr05","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Sleep disturbances are early hallmarks of Alzheimer\u2019s disease (AD) and other dementias, yet the molecular mechanisms remain poorly understood. We previously showed that dipeptidyl aminopeptidase-like protein 6-knockout (DPP6-KO) mice exhibit accelerated neurodegeneration with synaptic loss, neuronal death, and circadian dysfunction resembling AD pathology. Here, we investigate whether DPP6 deficiency directly causes sleep dysregulation and assess age-dependent effects using wireless EEG\/EMG telemetry, behavioral monitoring, and body temperature recordings. We found striking age-dependent sleep phenotypes in DPP6-KO mice. Adult (3-month) DPP6-KO mice showed hyperactivity-driven REM sleep increases, while aged (12-month) DPP6-KO mice developed insomnia with fragmented sleep architecture. Critically, aged DPP6-KO mice exhibited decreased REM latency, a biomarker of depression, which we confirmed by behavioral assays. Conversely, DPP6 overexpression in aged wild-type mice increased NREM duration and reduced sleep fragmentation, demonstrating a protective effect. Throughout aging, DPP6-KO mice showed dysregulated locomotor activity and body temperature rhythms, suggesting broader disruption of circadian and metabolic homeostasis. These findings establish DPP6 as a critical regulator of sleep architecture whose loss recapitulates key sleep disturbances observed in AD\/dementia. The progressive nature of sleep dysfunction in DPP6-KO mice, from REM abnormalities to insomnia, parallels human disease progression and positions DPP6 as a potential therapeutic target for sleep-related symptoms in neurodegenerative disorders.<\/jats:p>","DOI":"10.3390\/ijms27073224","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T11:51:03Z","timestamp":1775130663000},"page":"3224","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["DPP6 Loss Causes Age-Dependent Sleep Dysregulation and Depression-like Phenotypes Linked to Neurodegeneration"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0801-0671","authenticated-orcid":false,"given":"Lin","family":"Lin","sequence":"first","affiliation":[{"name":"Molecular Neurophysiology and Biophysics Section, Program in Developmental Neuroscience, <i>Eunice Kennedy Shriver<\/i> National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6458-7451","authenticated-orcid":false,"given":"Ashley E.","family":"Pratt","sequence":"additional","affiliation":[{"name":"Molecular Neurophysiology and Biophysics Section, Program in Developmental Neuroscience, <i>Eunice Kennedy Shriver<\/i> National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6999-2157","authenticated-orcid":false,"given":"Dax A.","family":"Hoffman","sequence":"additional","affiliation":[{"name":"Molecular Neurophysiology and Biophysics Section, Program in Developmental Neuroscience, <i>Eunice Kennedy Shriver<\/i> National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1152\/physrev.00010.2018","article-title":"The Sleep-Immune Crosstalk in Health and Disease","volume":"99","author":"Besedovsky","year":"2019","journal-title":"Physiol. 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