Effect of the ABCA1 agonist CS-6253 on amyloid-β and lipoprotein 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 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 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. 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 Aβ clearance from the brain.

The role of ATP‐binding cassette transporter G1 (ABCG1) in Alzheimer's disease: A review of the mechanisms

“…with the apoE4 allele). The development of CS‐6253 as a selective ABCA1 activator 169 implies that making selective ABCG1 activators is possible and may reduce discrepancies regarding ABCG1's role in AD. ABCG1's exact role in the development of AD and dementia needs to be clarified by further studies.…”

Cellular senescence induced by cholesterol accumulation is mediated by lysosomal ABCA1 in APOE4 and AD

“…Ion-mobility analysis HDL particles in mouse CSF and plasma were determined by ion mobility analysis as previously reported [37]. Samples treated with dextran sulfate were introduced into a charge-reducing electrospray (TSI Inc., model 3482) every 13 min by automated loop injections using an integrated autosampler (Teledyne CETAC Technologies, model MVX-7100).…”