Effect of the ABCA1 agonist CS-6253 on amyloid-β and lipoprotein metabolism in cynomolgus monkeys

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-beta peptides (A beta) 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 into 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 A beta 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 A beta 42/40 ratio were transiently increased following CS-6253 intravenous injection. This change was associated with a non-significant decrease in CSF A beta 42. Both plasma total cholesterol and HDL-cholesterol levels were reduced following treatment. AF4 fractionation revealed that 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: Treatment with the ABCA1 agonist CS-6253 appears to favor AP clearance from the brain.

Automated summary

This study investigated the effects of the ABCA1 agonist peptide CS-6253 on amyloid-beta peptides (Aβ) and lipoproteins in plasma and cerebrospinal fluid (CSF) of cynomolgus monkeys. The results showed that CS-6253 treatment increased small plasma high-density lipoprotein (HDL) particles and transiently increased plasma triglyceride (TG), apolipoprotein E (apoE), and Aβ 42/40 ratio. CS-6253 also displaced apoE from HDL to intermediate-density- and low-density-lipoprotein (IDL/LDL)-sized particles in plasma. However, CS-6253 had no effect on CSF apolipoproteins or lipids.