CHARACTERIZATION OF D-ENANTIOMERIC PEPTIDES BINDING TO MONOMERIC AMYLOID BETA (1-42) IDENTIFIED BY A COMPETITIVE MIRROR IMAGE PHAGE DISPLAY

Abstract

The aim of this study is to assess the convenience of exploring longterm synergistic effects when multiple AD therapeutics of different mechanisms, fundamental and symptomatic, are combined. Methods: As a symptomatic drug, we selected donepezil, which have significant clinical benefits by activating undamaged cholinergic systems. From our previous study, as a fundamental drug, we prepared a small molecule KMSB600 that disassembles neurotoxic Ab aggregates back to inert Ab monomers and reverses the behavioral deficits in 2xTG-AD mice (APP/ PS1). During the oral co-administration, we performed Y-maze tasks every week for 4 months and performed fear conditioning tasks after the last trial of Y-maze. Ab plaques were visualized by thioflavin-S staining. Results: Co-administration of donepezil and KMSB600 significantly improved the deficits in the both behavior tests and histology study, compared to individual administration of donepezil or KMSB600 at the same dosages. Conclusions: Here, we report that co-administration of donepezil and KMSB600 significantly enhanced cognitive deficits in aged-AD mice in a complementary manner. Our findings imply that the cure of AD may require cocktail therapy of multiple drugs with different modes of action: cholinergic system improvement and amyloidogenic pathology reduction.