Sleep disorders and Alzheimer's disease: relationship and mechanisms involving neuroinflammation, orexin and Aβ.

Aims: Sleep disorders are common in Alzheimer's disease (AD), but the underlying mechanisms are unknown. This study aimed to specifically investigate the relationship between a specific sleep disorder of short sleep duration (SSD) and AD, and related mechanisms involving neuroinflammation, orexin and AD biomarkers in both AD patients and mice.

Methods: In part I, total 247 AD patients were consecutively recruited and categorized into AD with SSD (AD-SSD, < 6 h) and AD with no SSD (AD-nSSD, 7-8 h). Comparisons were made between the two groups in cognitive function, neuroinflammatory factors, orexinergic factors and AD biomarkers in cerebrospinal fluid (CSF). The correlations of orexinergic factors with the neuroinflammatory factors and AD biomarkers in CSF from AD-SSD group were investigated. In part II, the spatiotemporal relationships among glial activation, orexin expression, AD pathology, sleep architecture disturbance and cognitive function in 5XFAD mice were dynamically explored and the potential mechanisms underlying their relationships were analyzed.

Results: In part I, compared to AD-nSSD group, AD-SSD group exhibited significantly poorer cognitive performance on the Montreal Cognitive Assessment and the Auditory Verbal Learning Test-delayed recall scales, higher orexin A level in CSF and lower β amyloid (Aβ) 42 level in CSF (all P < 0.05). Furthermore, orexin A had a positive correlation with prostaglandin E₂ (PGE₂) (r = 0.322, P = 0.002) and a negative correlation with Aβ42 (r = -0.223, P = 0.027) levels in CSF from AD-SSD group. In part II, compared with WT mice, 5XFAD mice displayed elevated hippocampal glial fibrillary acidic protein level at 3.5 months, increased hippocampal/cortical Chitinase-3-like protein 1 level, hypothalamic orexin A level and sleep architecture disturbance at 4.5 months, elevated insoluble Aβ42 deposition in hippocampus, orexinergic neuronal numbers in lateral hypothalamus, colocalization of their fibers with Aβ in cerebral cortex and cognitive impairment at 5.5 months old (all P < 0.05).

Conclusion: SSD in AD is associated with significant cognitive impairment, neuroinflammation, orexin elevation and Aβ deposition. Hippocampal astroglial activation, hypothalamic orexin elevation and sleep architecture disturbance precede Aβ deposition in hippocampus and cognitive impairment in 5XFAD mice.