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

Abstract

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.