In plasma, Aβ also interacts with apolipoprotein E (apoE), apolipoprotein A-I (apoA-I), or apolipoprotein C-III (apoC-III). Sequestration of Aβ by sLRP or by Aβ antibodies in the periphery can promote Aβ efflux from the brain. Aβ is cleared from the brain into the peripheral circulatory system. Cholesterol content of neurons is kept low, inhibiting Aβ accumulation. In the brain, neuronal production of Aβ is controlled by membrane cholesterol content. Aβ plaque brain deposition has been linked to cholesterol and lipid metabolism, both in the brain and in the periphery. Low plasma Aβ42/40 ratio has been associated with increased risk of dementia, more pronounced decline in cognitive function, and increased fibrillary Aβ deposition in the brain. The ratio of Aβ42 to Aβ40 in plasma is a promising biomarker for selecting patients with brain amyloid accumulation. Treatment with the ABCA1 agonist CS-6253 appears to favor Aβ clearance from the brain.ĭeposition of extra-cellular amyloid-β peptide (Aβ) plaques in the brain is a feature of Alzheimer’s disease (AD) pathology as Aβ monomers can aggregate, which form fibrils and senile plaques. In contrast to plasma, CS-6253 had no effect on the assessed CSF apolipoproteins or lipids. AF4 fractionation revealed that CS-6253 treatment displaced apoE from HDL to intermediate-density- and low density-lipoprotein (IDL/LDL)-sized particles in plasma. Both plasma total cholesterol and HDL-cholesterol levels were reduced following treatment. This change was associated with a non-significant decrease in CSF Aβ42. In two independent experiments, plasma TG, apolipoprotein E (apoE), and Aβ42/40 ratio were transiently increased following CS-6253 intravenous injection. Resultsįollowing CS-6253 intravenous injection, within minutes, small plasma high-density lipoprotein (HDL) particles were increased. The relationship between the change in levels of these biomarkers was analyzed using multiple linear regression models and linear mixed-effects models.
Levels of cholesterol, triglyceride (TG), lipoprotein particles, apolipoproteins, and Aβ were measured using ELISA, ion-mobility analysis, and asymmetric-flow field-flow fractionation (AF4). Plasma and CSF samples were collected at several time points before and after treatment. MethodsĬS-6253 peptide was injected intravenously into cynomolgus monkeys at various doses in three different studies. 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. Inducing brain ATP-binding cassette 1 (ABCA1) activity in Alzheimer’s disease (AD) mouse models is associated with improvement in AD pathology.
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