Mathematical model shows how sleep may affect amyloid β fibrillization

Abstract

Deposition of amyloid β (Aβ) fibers in extra-cellular matrix of the brain is a ubiquitous feature associated with several neurodegenerative disorders, especially Alzheimer's disease (AD). While many of the biological aspects that contribute to the formation of Aβ plaques are well addressed at the intra-and inter-cellular level in short timescales, an understanding of how Aβ fibrillization usually starts to dominate at a longer timescale in spite of the presence of mechanisms dedicated to Aβ 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 sleep-wake cycle. In this study, we develop a minimal model of Aβ fibrillization to investigate the onset of AD over a long time-scale. Our results suggest that the diseased state is a manifestation of a phase change of the system from soluble Aβ (sAβ) to fibrillar Aβ (fAβ) domination upon surpassing a threshold in the production rate of soluble Aβ. By incorporating the circadian rhythm into our model, we reveal that fAβ accumulation is crucially dependent on the regulation of sleep-wake cycle, thereby indicating the importance of a good sleep hygiene in averting AD onset. We also discuss potential intervention schemes to reduce fAβ accumulation in the brain by modification of the critical sAβ production rate.

Brain geometry matters in Alzheimer’s disease progression: a simulation study

“…In healthy condition, sAβ are mostly generated at the GM, and diffuse out to the CSF. However, they may sediment into amyloid plaques on their way if their production rate is higher than a critical value [29].…”

“…In the absence of amyloid plaques, soluble Aβ oligomers form small nuclei with a tiny nucleation rate k n . The growth of the nuclei occurs much faster with a polymerization rate k p which is greater than k n [44,29]. The growth of amyloid plaques can be prohibited by astrocytes through astrogliosis and scar formation, represented by A (see Eq.…”

“…We also found that there is a critical production rate beyond which the fibrillization occurs. The other parameters of the system regulate this critical rate [29].…”

“…Soluble Aβ can also discharge mechanically from the cerebrospinal fluid (CSF) [6,46,63] or meningeal lymphatics [14,30]. Nevertheless, the clearance of Aβ cannot tolerate production rates beyond a critical value [29]. This leads to the emergence of a critical production rate (Aβ concentration) over which the plaques form [29,19].…”

“…Nevertheless, the clearance of Aβ cannot tolerate production rates beyond a critical value [29]. This leads to the emergence of a critical production rate (Aβ concentration) over which the plaques form [29,19].…”