A novel apoE-mimetic increases brain apoE levels, reduces Aβ pathology and improves memory when treated before onset of pathology in male mice that express APOE3

Abstract

Background: Alzheimer's disease (AD) is characterized by cognitive dysfunction and amyloid plaques composed of the amyloid-beta peptide (Aβ). APOE is the greatest genetic risk for AD with APOE4 increasing risk up to ~ 15-fold compared to APOE3. Evidence suggests that levels and lipidation of the apoE protein could regulate AD progression. In glia, apoE is lipidated via cholesterol efflux from intracellular pools, primarily by the ATP-binding cassette transporter A1 (ABCA1). Therefore, increasing ABCA1 activity is suggested to be a therapeutic approach for AD. CS-6253 (CS) is a novel apoE mimetic peptide that was developed to bind and stabilize ABCA1 and maintain its localization into the plasma membrane therefore promoting cholesterol efflux. The goal of this study was to determine whether CS could modulate apoE levels and lipidation, Aβ pathology, and behavior in a model that expresses human APOE and overproduce Aβ.

Methods: In vitro, APOE3-glia or APOE4-glia were treated with CS. In vivo, male and female, E3FAD (5xFAD^+/-/APOE3^+/+) and E4FAD (5xFAD^+/-/APOE4^+/+) mice were treated with CS via intraperitoneal injection at early (from 4 to 8 months of age) and late ages (from 8 to 10 months of age). ApoE levels, ABCA1 levels and, apoE lipidation were measured by western blot and ELISA. Aβ and amyloid levels were assessed by histochemistry and ELISA. Learning and memory were tested by Morris Water Maze and synaptic proteins were measured by Western blot.

Results: CS treatment increased apoE levels and cholesterol efflux in primary glial cultures. In young male E3FAD mice, CS treatment increased soluble apoE and lipid-associated apoE, reduced soluble oAβ and insoluble Aβ levels as well as Aβ and amyloid deposition, and improved memory and synaptic protein levels. CS treatment did not induce any therapeutic benefits in young female E3FAD and E4FAD mice or in any groups when treatment was started at later ages.

Conclusions: CS treatment reduced Aβ pathology and improved memory only in young male E3FAD, the cohort with the least AD pathology. Therefore, the degree of Aβ pathology or Aβ overproduction may impact the ability of targeting ABCA1 to be an effective AD therapeutic. This suggests that ABCA1-stabilizing treatment by CS-6253 works best in conditions of modest Aβ levels.

Keywords: Alzheimer’s disease; CS-6253; EFAD mice; apoE.