P2-299: Oral administration of an apolipoprotein A-I–mimetic peptide improves cognitive function and reduces amyloid burden in a mouse model of Alzheimer disease

Abstract

Recent evidences indicate that inflammatory mechanisms represent a component that may significantly contribute to the progression of Alzheimer's disease (AD). Apo A-I mimetic peptide D-4F has been shown to inhibit atherosclerotic lesion formation and in presence of statin, even regresses already existing lesion. Oral administration of D-4F has also been shown to improve cognitive function and decreases brain arteriole inflammation in LDL receptor null mice on Western diet. Since this peptide is in phase II clinical trials for atheroscerosis prevention, we undertook a study to evaluate the efficacy of oral D-4F in presence of pravastatin on the improvement of cognitive performance and inhibition of amyloid β plaque burden in a mouse model of AD. 3 groups of 4 month old male APPswe-PS1ΔE9 Tg mice were used. The first group received D-4F (200μg/ml) + pravastatin (10μg/ml) in drinking water. The second group received a control peptide scrambled D-4F (Sc-D-4F, 200μg/ml) and pravastatin (10μg/ml) and the third group did not receive any drugs. After 3 months of treatment the mice were tested for their ability for spatial learning and retention using Morris Water Maze test. Amyloid burden occupied in the hippocampi was analysed by immunohistochemistry and inflammatory markers in the brain were measured by ELISA. Mice treated with D-4F +statin for 3 months showed a significant improvement in their spatial memory and retention (p< 0.01) compared to the other two groups. In control and Sc-D-4F+statin treated mice the hippocampus area occupied by amyloid plaque was 4.2±0.5% and 3.8±0.6% respectively, whereas in D-4F+statin treated mice the amyloid burden in hippocampus decreased significantly (1.6±0.2%, p< 0.001 vs control and p< 0.01 vs Sc-D-4F+statin group). Brain cytokine levels such as TNF–α and IL-1β levels were also reduced in D-4F administered group compared to the other two groups. In a mouse model of AD, D-4F+statin inhibits amyloid deposition in the hippocampus. Along with inhibition of amyloid plaque, the peptide also improves the hippocampal dependent spatial memory and retention. We also observed lower brain cytokine levels in the D-4F+ statin treated group. This can therefore be a potential therapy for AD.