Effect Of The ABCA1 Agonist CS-6253 On Amyloid β And Lipoproteins Metabolism In Cynomolgus Monkeys.

Abstract

Background: Inducing brain ATP binding cassette 1 (ABCA1) activity in Alzheimer’s disease (AD) mouse models is associated with improvement in AD pathology. The purpose of this study was to investigate the effects of the ABCA1 agonist peptide CS-6253 on amyloid-β peptides (Aβ) and lipoproteins in plasma and cerebrospinal fluid (CSF) of cynomolgus monkeys, a species with amyloid and lipoprotein metabolism similar to humans. Methods: CS-6253 peptide was injected intravenously to cynomolgus monkeys at various doses in three different studies. Plasma and CSF samples were collected at several time points before and after treatment. Levels of cholesterol, triglyceride (TG), lipoprotein particles, apolipoproteins, and Aβ were measured using ELISA, ion-mobility analysis, and asymmetric-flow field-flow fractionation (AF4). The relationship between the change in levels of these biomarkers was analyzed using multiple linear regression models and linear mixed-effects models.Results: Following CS-6253 intravenous injection, within minutes, small, plasma high-density lipoprotein (HDL) particles were increased. In two independent experiments, plasma TG, apolipoprotein E (apoE), and Aβ42/40 ratio were transiently increased following CS-6253 intravenous injection. This change was associated with a non-significant decrease in CSF Aβ42. Both plasma total cholesterol and HDL-cholesterol levels were reduced following treatment. Using AF4 fractionation, CS-6253 treatment displaced apoE from HDL to intermediate-density- and low density-lipoprotein (IDL/LDL) sized particles in plasma. In contrast to plasma, CS-6253 had no effect on the assessed CSF apolipoproteins or lipids.Conclusions: These findings support that inducing systemic ABCA1 activity by CS-6253 shifts apoE into larger triglyceride-rich lipoprotein (TRL) particles that assist in Aβ clearance from the brain.