Fig. 1: Six-compartment model of brain to plasma solute exchange.

A Amyloid β (Aβ) and tau are produced in neurons (1) and released into the ISF compartment (2) where they are cleared from the ISF via local cellular uptake (2 → 5) and degradation, blood-brain barrier efflux (2 → 4), or glymphatic efflux to the CSF (2 → 3). Aβ42 and phosphorylated tau species are prone to non-monomeric aggregation, unlike Aβ40 and non-phosphorylated tau. Their monomeric forms can also be cleared from the ISF through further aggregation into non-monomeric structures (2 → 6). CSF solutes may recirculate back into the brain interstitium (3 → 2) or be cleared by CSF efflux pathways to the plasma (3 → 4) from whence peripheral degradation occurs. B–C Compartment concentrations of monomeric amyloid β and tau at steady state in the null model and the neuro-glymphatic model following changes in glymphatic efflux/influx or synaptic and metabolic release. Release of cellular Aβ and tau species from neurons (1) into the ISF (2) in the model is controlled by the cellular solute release rate constant \({k}_{{cell\_rel}}\) and was kept constant during the 16 hours of wake and was reduced by 30% during the 8 h of sleep occurring in the shaded window between 16 and 24 h. Solid lines show compartment concentrations under the null model, with time-invariant release rate constant \({k}_{{cell\_rel}}\) and time-invariant exchange between the CSF (3) and ISF (2) compartments. Long dashed lines show change in compartment concentrations when glymphatic efflux/influx rate constants \({k}_{{glymph\_out}}\) and \({k}_{{glymph\_in}}\), were increased by a factor of 1.5 (B) or decreased by a factor 0.5 (C) during the 8-hour sleep window. Dotted lines show change in compartment concentrations when synaptic and metabolic release rate constant \({k}_{{cell\_rel}}\) was increased by a factor of 1.25 (B) or decreased by a factor of 0.5 (C) during the 8-h sleep window. Note that increasing (decreasing) either glymphatic efflux/influx or synaptic and metabolic release during sleep increases (decreases) morning plasma level of Aβ and tau species relative to the null model.