Interplays between different secretases in the generation of Amyloid-β lead to the emergence of ‘Amyloid-β rise’

The abnormal accumulation of Amyloid-β (Aβ) initials the pathological progress of Alzheimer’s disease (AD). γ-secretase, which is a key secretase involving in the formation of Aβ, becomes one of candidate therapeutic targets for preventing the pathological progress of AD. In order to reduce the amount of Aβ in brain, different types of γ-secretase inhibitor were designed to limit the catalytic rate of γ-secretase. However, there is a paradoxical phenomenon called ‘Aβ rise’ can be found in experiment. In this phenomenon, the amount of Aβ will rise as the lower levels of γ-secretase inhibitor is added, which hinders the development of related drugs. In present paper, a mathematical model based on the generation of Aβ is proposed to explore the biological mechanism of ‘Aβ rise’. Through rigorous analysis about the dynamic behavior for this model, we firstly obtain the index for the emergence of ‘Aβ rise’. Furthermore, the analysis results show that both the inhibition of C-terminal fragment (C99) to α-secretase cleavage of amyloid precursor protein (APP) and the lower γ-secretase independent degradation for C99 are contributed to ‘Aβ rise’. Hence, enhancing the intensity of γ-secretase independent degradation of C99 can effectively block the appearance of ‘Aβ rise’. These findings will give new insights on the arise of ‘Aβ rise’ and therapeutic strategies for AD. •‘Amyloid-β rise’ is a contradictory phenomenon, in which drugs do not effectively inhibit the increase of Amyloid-β, but accelerate its increase. It directly hinders the drug development, which strongly affects the treatment for Alzheimer’s Disease.•A nonlinear system based on the mechanism of Amyloid-β is built in our manuscript. Through rigorous nonlinear theoretical analysis, we found that the change trend of equilibrium with the rise of concentration of drugs present complex dynamical behaviors: monotone somewhere or non-monotone.•Both the inhibition of C-terminal fragment to α-secretase cleavage of amyloid precursor protein and the lower γ-secretase independent degradation for C-terminal fragment are contributed to ‘Amyloid-β rise’.