Mathematical Model Shows How Sleep May Affect Amyloid-ß Fibrillization.

Deposition of amyloid-ß (Aß) fibers in the extracellular matrix of the brain is a ubiquitous feature associated with several neurodegenerative disorders, especially Alzheimer's disease (AD). Although many of the biological aspects that contribute to the formation of Aß plaques are well addressed at the intra- and intercellular levels in short timescales, an understanding of how Aß fibrillization usually starts to dominate at a longer timescale despite the presence of mechanisms dedicated to Aß clearance is still lacking. Furthermore, no existing mathematical model integrates the impact of diurnal neural activity as emanated from circadian regulation to predict disease progression due to a disruption in the sleep-wake cycle. In this study, we develop a minimal model of Aß fibrillization to investigate the onset of AD over a long timescale. Our results suggest that the diseased state is a manifestation of a phase change of the system from soluble Aß (sAß) to fibrillar Aß (fAß) domination upon surpassing a threshold in the production rate of sAß. By incorporating the circadian rhythm into our model, we reveal that fAß accumulation is crucially dependent on the regulation of the sleep-wake cycle, thereby indicating the importance of good sleep hygiene in averting AD onset. We also discuss potential intervention schemes to reduce fAß accumulation in the brain by modification of the critical sAß production rate.