Orexin-A and Circadian Disruption in Alzheimer's Disease: Implications for Amyloid-Beta Pathology

Alzheimer's disease (AD) is characterized by cognitive decline, circadian rhythm disruptions, and accumulation of Aβ plaques. Orexin-A, a neuropeptide involved in regulating sleep and circadian rhythms, has been implicated in these processes, although its specific role in modulating β-amyloid (Aβ) aggregation remains unclear. This study investigates how orexin-A influences Aβ aggregation and its impact on cognitive and circadian dysfunctions in AD mice subjected to acute sleep deprivation (ASD). Behavioural assessments showed significant cognitive deficits following ASD, including impaired recognition and spatial memory. Proteomic analysis revealed 1380 modulated proteins, including 105 associated with AD, 56 with cognitive functions, 11 with circadian rhythm, and six involved in Aβ clearance. Further analysis showed dysregulation of Clock and Bmal1 levels, along with reduced orexin-A expression after ASD. Since orexin-A regulates both sleep and circadian rhythm, investigating its role in modulating Aβ aggregation is essential for understanding the pathophysiology of AD. To explore this, we performed molecular dynamics (MD) simulations to gain insights into the molecular interactions between orexin-A and Aβ. Analysis revealed that orexin-A binds Aβ with high affinity and effectively inhibits its aggregation, suggesting a potential mechanism for reducing Aβ-induced neurotoxicity. These results suggest that orexin-A may play an important role in modulating Aβ aggregation and circadian dysfunction in AD, as supported by simulation results. Further studies manipulating orexin-A levels are needed to confirm its role in this context. Our findings highlight orexin-A as a potential therapeutic target for slowing cognitive decline and neurodegeneration in AD by restoring circadian and sleep-wake regulation.