Noveir, Sasan D;
Kerman, Bilal E;
Xian, Haotian;
Meuret, Cristiana;
Smadi, Sabrina;
Martinez, Ashley E;
Johansson, Johannes;
... Yassine, Hussein N; + view all
(2022)
Effect of the ABCA1 agonist CS-6253 on amyloid-beta and lipoprotein metabolism in cynomolgus monkeys.
Alzheimer's Research & Therapy
, 14
(1)
, Article 87. 10.1186/s13195-022-01028-1.
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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.
| Type: | Article |
|---|---|
| Title: | Effect of the ABCA1 agonist CS-6253 on amyloid-beta and lipoprotein metabolism in cynomolgus monkeys |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1186/s13195-022-01028-1 |
| Publisher version: | https://doi.org/10.1186/s13195-022-01028-1 |
| Language: | English |
| Additional information: | Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Clinical Neurology, Neurosciences, Neurosciences & Neurology, ABCA1, Apolipoprotein E, Alzheimer's disease, CS-6253, APOLIPOPROTEIN-A-I, SPORADIC ALZHEIMERS-DISEASE, RECEPTOR-RELATED PROTEIN-1, COGNITIVE DECLINE, PRECURSOR PROTEIN, HEPATIC LIPASE, MOUSE MODEL, LC-MS/MS, CHOLESTEROL, PLASMA |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10151854 |
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