Analysis of the Amyloid Cascade after b-Secretase Inhibition Enables the Identification of an A b 42 Oligomer Pool s

The deposition of amyloid-b (Ab) 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 after administration of three different doses (10, 30, and 125 mg/kg) of the b-secretase 1 (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 Ab42, Ab40, soluble b-amyloid precursor protein (sAPP) a, and sAPPb in CSF. The systems pharmacology model contained expressions to describe the production, elimination, and brain-to-CSF transport for the APP metabolites. Upon administration of MBi-5, a dose-dependent increase of the metabolite sAPPa and dose-dependent decreases of sAPPb and Ab were observed. Maximal inhibition of BACE1 was close to 100% and the IC50 value was 0.0256 mM (95% confidence interval, 0.0137–0.0375). A differential effect of BACE1 inhibition on Ab40 and Ab42 was observed, with the Ab40 response being larger than the Ab42 response. This enabled the identification of an Ab42 oligomer pool in the systems pharmacology model. These findings indicate that decreases in monomeric Ab responses resulting from BACE1 inhibition are partially compensated by dissociation of Ab oligomers and suggest that BACE1 inhibition may also reduce the putatively neurotoxic oligomer pool.