Jan O. Johansson, Anat Boehm‐Cagan, John K. Bielicki1, Daniel M. Michaelson
1Lawrence Berkeley Laboratory, Berkeley, CA
Tóm tắt
Background:
Apolipoprotein E4 (apoE4) is associated with perturbed lipid metabolism and elevated risk for CVD and Alzheimer’s disease (AD). Data suggests impact of both non-brain and brain apoE on risk to develop AD. Homozygosity for apoE4 increases AD risk approximately 10-fold. Brain apoE4particles are smaller and less lipidated than brain apoE2 or apoE3. ApoE is lipidated by ATP Binding Cassette A1 (ABCA1) and both proteins are synthesized predominantly in astrocytes. We hypothesized that enhancing apoE4 lipidation by an ABCA1 agonist, CS6253, would have AD therapeutic actions.
Methods and Results:
Astrocyte cholesterol efflux is highly responsive to stimulation by exogenous CS6253 peptide. Time-course showed that basal [3H]cholesterol efflux from cells to serum-free medium was compromised in apoE4 astrocytes. Incubating with peptide CS6253 (10 μg/mL) showed 6-fold improvement in [3H] cholesterol efflux to serum-free medium containing either apoE4 or E3 astrocytes. CS6253 crossed the BBB and was found to co-localize with astrocytes in hippocampus. CS6253 i.p. injection (20 mg/kg/48h for 6 weeks) in apoE4 Targeted Replacement mice significantly lowered apoJ in plasma and the brain. The distribution of serum apoE4 on HPLC to smaller lipoproteins was seen rendering similar profile to apoE3. Plasma apoA-I levels, cholesterol and triglyceride levels were unchanged. Lipidation of apoE in brain was compromised in apoE4 compared to apoE3 mice and CS6253 treatment increased apoE4 lipidation. CS6253 treatment prevented cognition decline and development of the brain AD pathological phenotype. CS6253 treatment decreased Aβ42 and P-tau and increased levels of VGluT1 and apoER2. Cognitive decline was fully prevented in apoE4 mice by CS6253 treatment as assessed by novel object recognition and Morris water maze.
Conclusion:
ABCA1 agonist treatment by CS653 resulted in improved apoE4 lipidation in cells and in mice. Six weeks treatment counteracted apoE4 driven AD with regard to phenotype and cognition. The data point to the potential therapeutic utility of CS6253 in apoE4 AD.
