The deposition of amyloid-β oligomers in brain parenchyma has been implicated in the pathophysiology of Alzheimer's disease. Here we present a systems pharmacology model describing the changes in the amyloid precursor protein (APP) pathway following administration of three different doses (10, 30 and 125 mg/kg) of the β-secretase (BACE1) inhibitor MBi-5 in cisterna magna ported rhesus monkeys. The time course of the MBi-5 concentration in plasma and cerebrospinal fluid (CSF) was analyzed in conjunction with the effect on the concentrations of the APP metabolites Aβ42, Aβ40, sAPPα and sAPPβ in CSF. The systems pharmacology model contained expressions to describe the production, elimination and brain-to-CSF transport for the APP metabolites. Upon the administration of MBi-5 a dose dependent increase of the metabolite sAPPα and dose dependent decreases of sAPPβ and Aβ were observed. Maximal inhibition of BACE1 was close to 100% and the value of the IC50 was 0.0256 μM (95% CI, 0.0137-0.0375). A differential effect of BACE1 inhibition on Aβ40 and Aβ42 was observed, with the Aβ40 response being larger than the Aβ42 response. This enabled the identification of an Aβ42 oligomer pool in the systems pharmacology model. These findings indicate that decreases in monomeric Aβ responses resulting from BACE1 inhibition are partially compensated by dissociation of Aβ oligomers and suggest that BACE1 inhibition may also reduce the putatively neurotoxic oligomer pool.
- The American Society for Pharmacology and Experimental Therapeutics