Modeling Effect of a γ-Secretase Inhibitor on Amyloid-β Dynamics Reveals Significant Role of an Amyloid Clearance Mechanism

Aggregation of the small peptide amyloid beta (A beta) into oligomers and fibrils in the brain is believed to be a precursor to Alzheimer's disease. A beta is produced via multiple proteolytic cleavages of amyloid precursor protein (APP), mediated by the enzymes beta- and gamma-secretase. In this study, we examine the temporal dynamics of soluble (unaggregated) A beta in the plasma and cerebral-spinal fluid (CSF) of rhesus monkeys treated with different oral doses of a gamma-secretase inhibitor. A dose-dependent reduction of A beta concentration was observed within hours of drug ingestion, for all doses tested. A beta concentration in the CSF returned to its predrug level over the monitoring period. In contrast, A beta concentration in the plasma exhibited an unexpected overshoot to as high as 200% of the predrug concentration, and this overshoot persisted as late as 72 hours post-drug ingestion. To account for these observations, we proposed and analyzed a minimal physiological model for A beta dynamics that could fit the data. Our analysis suggests that the overshoot arises from the attenuation of an A beta clearance mechanism, possibly due to the inhibitor. Our model predicts that the efficacy of A beta clearance recovers to its basal (pretreatment) value with a characteristic time of > 48 hours, matching the time-scale of the overshoot. These results point to the need for a more detailed investigation of soluble A beta clearance mechanisms and their interaction with A beta-reducing drugs.