Recognition and Removal of Amyloid-β by a Heteromultivalent Macrocyclic Coassembly: A Potential Strategy for the Treatment of Alzheimer's Disease

Abstract

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, a coassembly composed of cyclodextrin (CD) and calixarene (CA) is designed, and it is used as an anti-Aβ therapy agent. The CD-CA coassembly is based on the previously reported heteromultivalent recognition strategy and is able to successfully eliminate amyloid plaques and degrade Aβ_1-42 monomers in 5xFAD mice. More importantly, the coassembly improves recognition and spatial cognition deficits, and synaptic plasticity impairment in the 5xFAD mice. In addition, the coassembly ameliorates AD-like pathology including prevention of neuronal apoptosis and oxidant stress, and alteration of M1/M2 microglial polarization states. This supramolecular approach makes full use of both molecular recognition and self-assembly of macrocyclic amphiphiles, and is a promising novel strategy for AD treatment.

Keywords: Alzheimer's disease; amyloid plaques; cognition; heteromultivalent recognition; pathological impairment.