Computational modeling of the effects of autophagy on amyloid-β peptide levels

Abstract

Autophagy is an evolutionarily conserved intracellular process that is used for delivering proteins and organelles to the lysosome for degradation. For decades, autophagy has been speculated to regulate amyloid-β peptide (Aβ) accumulation, which is involved in Alzheimers disease (AD); however, specific autophagic effects on the Aβ kinetics only have begun to be explored.

We develop a mathematical model for autophagy with respect to Aβ kinetics and perform simulations to understand the quantitative relationship between Aβ levels and autophagy activity. In the case of an abnormal increase in the Aβ generation, the degradation, secretion, and clearance rates of Aβ are significantly changed, leading to increased levels of Aβ. When the autophagic Aβ degradation is defective in addition to the increased Aβ generation, the Aβ-regulation failure is accompanied by elevated concentrations of autophagosome and autolysosome, which may further clog neurons.

The model predicts that modulations of different steps of the autophagy pathway (i.e., Aβ sequestration, autophagosome maturation, and intralysosomal hydrolysis) have significant step-specific and combined effects on the Aβ levels and thus suggests therapeutic and preventive implications of autophagy in AD.