The imbalance of amyloid-β (Aβ) production and clearance causes aggregation of Aβ_1-42 monomers to form fibrils and amyloid plaques, which is an indispensable process in the pathogenesis of Alzheimer’s disease (AD), and eventually leads to pathological changes and cognitive impairment. Consequently, Aβ_1-42 is the most important target for the treatment of AD. However, developing a single treatment method that can recognize Aβ_1-42, inhibit Aβ_1-42 fibrillation, eliminate amyloid plaques, improve cognitive impairments, and alleviate AD-like pathology is challenging. Here we designed a co-assembly composed of cyclodextrin (CD) and calixarene (CA), and used it as an anti-Aβ therapy agent. The CD-CA co-assembly was based on our previously reported heteromultivalent recognition strategy and was able to successfully eliminate amyloid plaques and degrade Aβ_1-42 monomers in 5xFAD mice. More importantly, the co-assembly improved the recognition and spatial cognition deficits through the Morris water maze (MWM) test and novel object recognition (NOR) test. Moreover, the co-assembly enhanced the field excitatory postsynaptic potential (fEPSP) slopes after theta burst stimulation (TBS) in 5xFAD mice, which correlates with the expression of Ν-methyl-D-aspartate (NMDA) receptor channels. In addition, the co-assembly ameliorated AD-like pathology including prevention of neuronal apoptosis and oxidant stress, and alteration of M1/M2 microglial polarization states. This supramolecular approach made full use of both molecular recognition and self-assembly of macrocyclic amphiphiles, and is a promising novel strategy for AD treatment.
 

Alzheimer’s disease,heteromultivalent recognition,amyloid plaques,cognition,NMDA receptor channels