Figure 2.

Details of submodels and their integration within quantitative systems pharmacology model. (a) Amyloid precursor protein (APP) processing model based on two published models to describe the production of amyloid beta (Aβ), p3, and AICD. (b) Cholesterol metabolism model diagram. Model mainly based on the production of cholesterol from pyruvate and acetyl‐CoA through the synthesis of HmgCoA and mevalonate as proposed by ref. 7. The 24‐OHC production is modeled using kinetic information reported by ref. 29. (c) Sphingolipid metabolism in the brain. Ceramide is proposed as a key apoptotic stimulator and is derived from palmitoyl‐coA from a reaction catalyzed by serine palmitoyltransferase. Ceramide equilibrates with sphingomyelin and sphingosine, catalyzed by sphingomyelinase and ceramide synthase. In turn, sphingosine can equilibrate with sphingosine‐1‐phosphate (S1P) catalyzed by sphingosine kinase. S1P is proposed to contribute to increased cell survival. (d) High‐level diagram of integration of the different sub‐models within the quantitative systems pharmacology model. CSF, cerebrospinal fluid.