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.
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