T. Karelina,1 O. Demin,1 S. Divvuri,2 T. Nicholas3; 1Institute for Systems Biology, Moscow, Russian Federation, 2Pfizer R&D, Groton, CT, 3Pfizer Global R&D, Groton, CT
BACKGROUND: Amyloid beta (Aβ) in its soluble and insoluble forms is considered a trigger and biomarker of Alzheimer's disease (AD), although protective functions of Aβ are also known. Thus optimal therapy should keep Aβ levels close to physiological levels of healthy subjects. The aim of this work was to search for optimal therapy using quantitative model.
METHODS: Proposed mechanistic longitudinal model of amyloid pathology was successfully calibrated on the variety of human data for CSF, brain and plasma. Transition to AD after 60 years is implemented by explicit longitudinal change of some of the model parameters: Aβ synthesis, destruction of plaques, transport.
RESULTS: Inhibition of synthesis by gamma secretase inhibitors (GSI) and activation insoluble Aβ destruction were simulated (Figure a,b). We considered cutting regime (CR, constant dose) and progressive regime (PR) with dose calculated by longitudinal progression function. With plaque decrease (Figure a) destruction CR leads to soluble Aβ increase, which can be smoothed by using PR (Figure b). Therapy by GSI leads to dramatic decrease of soluble Aβ (Figure b), but it also can be smoothed by PR without allowing insoluble forms to overcome level of healthy subjects.
CONCLUSION: Progressive therapeutic regimes allow keeping quantities of Aβ in physiological limits of healthy subjects.