DPP6 Loss Causes Age-Dependent Sleep Dysregulation and Depression-like Phenotypes Linked to Neurodegeneration.

Sleep disturbances are early hallmarks of Alzheimer's 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.