Quantitative systems pharmacology model of amyloid and tau to explore efficacy of therapy targeting modified forms of amyloid

Abstract

AbstractBackgroundAmyloid targeting therapy in different variations is still under development. One of the potential targets is modified forms of amyloid, Ab3p. They are very specific marker found in plaques of AD subjects, and demonstrate higher toxicity to neurons. Its correlation with tau load and AD severity is stronger than for non‐modified forms. Specific therapy targeting modified Ab may be more effective and less toxic due to lower required concentration of antibodies. Glutaminyl cyclase (QC) inhibitors have considerable BBB penetration and concomitant anti‐inflammatory activities. Monoclonal antibodies to specific to pGlu3‐Ab successfully reduce cognitive impairment in preclinical settings. Quantitative systems pharmacology QSP model is a good tool to study contribution of protein modification to disease progression and investigating sensitivity of overall system to specific targeting.MethodQSP model was developed to describing amyloid production and distribution, hetero‐oligomerization of Ab1‐40, Ab1‐42 and pGlu3‐Ab. It has been combined with description of tau pathology and neuron homeostasis (NH) model. NH model describes processes regulating protein degradation and transport. Modified amyloid polymerizes with higher rate and resistant to degradation. Rate of amyloid modification was assumed to be one of the drivers, depending on age (we assumed it can be related to the calcium EPR stress in neurons and microglia activation due to inflammatory stimuli). Amyloid and tau during accumulation disrupt transport, proteasomal and autolysosome system. The model was calibrated on multiple in vitro and in vivo data, as well as preclinical and clinical data for treatments by immunotherapies.ResultIntegrated model describes accumulation of amyloid and tau according to Braak stages. It captures the role of intraneuronal processes on tau and amyloid metabolism. Model describes influence of amyloid modification on total accumulation of amyloid. Both QC inhibition and targeting by antibodies attenuate accumulation of amyloid in brain. Tau pathology progression is reduced, assuming that binding of antibody prevents toxicity of pGlu3‐Ab on tau kinase activation and calcium influx.ConclusionModel can be used to analyze contribution of different amyloid forms to pathology and efficacy of specific therapies on multiple biomarkers. It can be used for explorations of different combinations and regimens.