Effect of the ABCA1 agonist CS-6253 on amyloid-β and lipoprotein metabolism in cynomolgus monkeys.
ABCA1
Alzheimer’s disease
Apolipoprotein E
CS-6253
Journal
Alzheimer's research & therapy
ISSN: 1758-9193
Titre abrégé: Alzheimers Res Ther
Pays: England
ID NLM: 101511643
Informations de publication
Date de publication:
24 06 2022
24 06 2022
Historique:
received:
12
11
2021
accepted:
07
06
2022
entrez:
24
6
2022
pubmed:
25
6
2022
medline:
29
6
2022
Statut:
epublish
Résumé
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. 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. 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. Treatment with the ABCA1 agonist CS-6253 appears to favor Aβ clearance from the brain.
Sections du résumé
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.
Identifiants
pubmed: 35751102
doi: 10.1186/s13195-022-01028-1
pii: 10.1186/s13195-022-01028-1
pmc: PMC9229758
doi:
Substances chimiques
ABCA1 protein, human
0
ABCA1 protein, mouse
0
ATP Binding Cassette Transporter 1
0
Amyloid beta-Peptides
0
Apolipoproteins
0
Apolipoproteins E
0
CS-6253
0
Peptides
0
Cholesterol
97C5T2UQ7J
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
87Subventions
Organisme : NIA NIH HHS
ID : R01 AG067063
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG056518
Pays : United States
Organisme : NIA NIH HHS
ID : R44 AG076299
Pays : United States
Organisme : NIA NIH HHS
ID : R44AG060826
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG076124
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG054434
Pays : United States
Organisme : NIA NIH HHS
ID : P50 AG005142
Pays : United States
Organisme : NIA NIH HHS
ID : R44 AG060826
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG055770
Pays : United States
Informations de copyright
© 2022. The Author(s).
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