The accumulation of amyloid â (Aâ) peptides as toxic oligomers, amyloid plaques and cerebral amyloid angiopathy (CAA) is critical in the causation of Alzheimer's disease (AD). The binding of Aâ peptides to apolipoprotein (apo) E plays an important role in modulation of amyloid deposition and clearance. We have previously shown that blocking the Aâ/apoE interaction by Aâ12-28P, a nontoxic blood-brain-barrier permeable and non-fibrillogenic synthetic peptide, constitutes a novel therapeutic approach for AD by reducing Aâ parenchymal deposition in an AD model, APP/PS1 Tg mice. In a recent study we have also shown that Aâ12-28P can greatly reduce vascular amyloid deposits in a Tg model (TgSwDI) of CAA, as well as Aâ oligomers. These findings suggest that blocking the Aâ/apoE interaction is a highly effective therapeutic approach for vascular amyloid deposition, in contrast to some other therapeutic approaches. In this proposed project, we will develop safe and more effective peptidomimetic antagonists of the Aâ/apoE interaction that will be derived from the Aâ12-28P sequence. Peptoid compounds due to their inherent resistance to degradation are known to have more favorable biological properties. The lead peptidomimetic will be tested in vivo using 3xTg mice with both amyloid and tau pathology, as well as in TgSwDI mice crossed onto human apoE3 or E4 or apoE KO backgrounds. These experiments will provide critical data prior to any testing of our compounds in non-human primates or human Phase I clinical trials.