Sex-specific acceleration of Alzheimer's pathogenesis by chronic sleep-deprivation.

INTRODUCTION: Sleep impairments likely contribute to Alzheimer's pathology, though specific contributions to disease progression are incompletely understood. We propose that autophagic impairment is associated with chronic sleep disruption and examine how sleep loss and stress influence disease development, including having impacts on proteostasis, cognition, and neural circuitry. METHODS: We sleep-disrupted 6-month-old APPNL-G-F mice for 2 weeks and behaviorally assessed sleep recovery, nesting, stress, and cognition. Subsequently, we analyzed markers of Alzheimer's pathology, stress, neuroinflammation, and proteostasis in hippocampal and subcortical brain regions. RESULTS: Sleep-deprived mice had altered sleep-related behaviors, increased stress, and signs of disease-acceleration including sex-dependent neurodegeneration, proteinopathy, and changes to autophagy and the neuroinflammatory response. DISCUSSION: Chronic sleep disruption accelerates the pathological cascade of Alzheimer's, including cognitive impairment and Alzheimer's pathology in a sex-dependent manner. This work enhances our understanding of the sleep-stress-Alzheimer's relationship, including sex-based differences, and may point to a novel therapeutic avenue to limit Alzheimer's progression.