Inheritance of the apolipoprotein (apo) E4 isoform is a major risk factor for sporadic Alzheimer's disease (AD). ApoE, especially its E4 isoform, can act as a pathological chaperone of beta-amyloid (Abeta) promoting its conformational transformation from soluble Abeta into toxic Abeta aggregates which accumulate in the form of plaques or in vascular walls. It is known that the binding site of apoE on Abeta corresponds to residues 12-28. To block this binding, we synthesized a peptide, Abeta12-28P, which is homologous to residues 12-28 of Abeta but with the valine at residue 18 was substituted by a proline. This renders this peptide non-toxic and non-fibrillogenic. Abeta12-28P is blood-brain-barrier permeable (clearance=65+/-20 mu l serum/gr.brain) and its end-protected version has a serum half-life of 62.2+/- 18 min. We have gathered extensive preliminary data demonstrating that Abeta12-28P reduces Abeta toxicity and fibril formation both in vitro and in vivo. Transgenic (Tg) APP/PS1 AD mice treated for one month with Abeta12-28P demonstrated a reduction in Abeta load by 63.3% in the cortex and by 61.9% (p=0.0048) in the hippocampus (p=0.0047) comparing to age matched Tg mice which received placebo. No antibodies against Abeta were detected in the sera of treated mice; therefore, the observed therapeutic effect of this peptide cannot be attributed to an antibody clearance response. No toxicity was observed in treated animals. In this research proposal we plan to extend our preliminary work, determining if treatment with our lead compound blocking apoE/Abeta interaction is a viable therapeutic approach for reducing Abeta deposition in AD using different animal models including double Tg mice co-expressing APP and various isoforms of human apoE on a murine apoE knock-out background. Behavioral testing, histological and biochemical analysis of Abeta load will be end points of this study. Two-photon microscopy will be used to follow the treatment effect in Tg mice in vivo. We are also planning to identify the location and structure of the Abeta binding site on apoE which is crucial for the development additional compounds which may block the apoE/Abeta interaction.