2. Academic Validation
  3. Effect of the ABCA1 agonist CS-6253 on amyloid-β and lipoprotein metabolism in cynomolgus monkeys

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

  • Alzheimers Res Ther. 2022 Jun 24;14(1):87. doi: 10.1186/s13195-022-01028-1.
Sasan D Noveir 1,  Bilal E Kerman 1,  Haotian Xian 1,  Cristiana Meuret 1,  Sabrina Smadi 1,  Ashley E Martinez 1,  Johannes Johansson 2,  Henrik Zetterberg 3 4 5 6 7,  Bryan A Parks 8,  Zsuzsanna Kuklenyik 8,  Wendy J Mack 9,  Jan O Johansson 10,  Hussein N Yassine 11
Affiliations

Affiliations

  • 1 Departments of Medicine and Neurology, University of Southern California, Los Angeles, CA, 90033, USA.
  • 2 Artery Therapeutics, Inc., San Ramon, CA, 94583, USA.
  • 3 Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
  • 4 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
  • 5 Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
  • 6 UK Dementia Research Institute at UCL, London, UK.
  • 7 Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
  • 8 Centers for Disease Control and Prevention, Atlanta, GA, 30341, USA.
  • 9 Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, 90033, USA.
  • 10 Artery Therapeutics, Inc., San Ramon, CA, 94583, USA. jjohansson@arterytx.com.
  • 11 Departments of Medicine and Neurology, University of Southern California, Los Angeles, CA, 90033, USA. Hyassine@usc.edu.
PMID: 35751102 DOI: 10.1186/s13195-022-01028-1
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.

Keywords

ABCA1; Alzheimer’s disease; Apolipoprotein E; CS-6253.

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