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.
Carrying the apolipoprotein E (ApoE) Ɛ4 allele is associated with an increased risk of cerebral amyloidosis and late-onset Alzheimer’s disease, but the degree to which apoE glycosylation affects its development is not clear. In a previous pilot study, we identified distinct total and secondary isoform-specific cerebral spinal fluid (CSF) apoE glycosylation profiles, with the E4 isoform having the lowest glycosylation percentage (E2 > E3 > E4). In this work, we extend the analysis to a larger cohort of individuals (n = 106), utilizing matched plasma and CSF samples with clinical measures of AD biomarkers. The results confirm the isoform-specific glycosylation of apoE in CSF, resulting from secondary CSF apoE glycosylation patterns. CSF apoE glycosylation percentages positively correlated with CSF Aβ42 levels (r = 0.53, p < 0.0001). These correlations were not observed for plasma apoE glycosylation. CSF total and secondary apoE glycosylation percentages also correlated with the concentration of CSF small high-density lipoprotein particles (s-HDL-P), which we have previously shown to be correlated with CSF Aβ42 levels and measures of cognitive function. Desialylation of apoE purified from CSF showed reduced Aβ42 degradation in microglia with E4 > E3 and increased binding affinity to heparin. These results indicate that apoE glycosylation has a new and important role in influencing brain Aβ metabolism and can be a potential target of treatment.
BackgroundATI has discovered a novel molecule, CS6253, for hereditary Apolipoprotein E4 (ApoE4) associated Alzheimer’s disease (AD), which is highly differentiated from other molecules in development by its focus on cholesterol transport. CS6253 is a 26mer peptide optimized for ATP binding cassette transporter A1 (ABCA1) mediated cholesterol efflux, in the brain a rate‐limiting step in cholesterol transport from cells to ApoE. ABCA1 activity, as well as CS6253 in AD mouse models, is associated with improvement in AD pathology.In preparation for human studies, we investigated the effects of the ABCA1 agonist peptide CS6253 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.MethodsCS6253 peptide was injected intravenously to cynomolgus monkeys at various doses in three different studies, 1) a pharmacokinetics (PK) study, 2) a dose‐range finding (DRF) study, and 3) a 30‐day Good Laboratory Practice (GLP) toxicology study. 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.ResultsCS6253 intravenous injection, within minutes, induced an increase in small, plasma high‐density lipoprotein (HDL) particles. Plasma TG, ApoE, and Aβ42/40 ratio were transiently increased following CS‐6253 intravenous injection, and a non‐significant decrease in CSF APP and Aβ42 was observed. CS‐6253 in plasma displaced ApoE from HDL to intermediate‐density‐ and low density‐lipoprotein (IDL/LDL) sized particles paralleled by transient reductions in total cholesterol and HDL‐cholesterol. In contrast to plasma, CS6253 had no effect on the assessed CSF apolipoproteins or lipids.ConclusionsIn cynomolgus monkeys administration of the ABCA1 agonist CS6253 transiently increased plasma ApoE and TGs which was paralleled by plasma Aβ42/40 ratio increase, providing a strong rationale for following these markers in ensuing human studies.
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.
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