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

Wang, H (Wang, Hui)^{[ 1,2 ]} ; Xu, XX (Xu, XinXin)^{[ 1,2 ]} ; Pan, YC (Pan, Yu-Chen)^{[ 3 ]} ; Yan, YX (Yan, YuXing)^{[ 1,2 ]} ; Hu, XY (Hu, Xin-Yue)^{[ 3 ]} ; Chen, RW (Chen, RunWen)^{[ 1,2 ]} ; Ravoo, BJ (Ravoo, Bart Jan)^{[ 4,5 ]} ; Guo, DS (Guo, Dong-Sheng)^{[ 3 ]} ; Zhang, T (Zhang, Tao)^{[ 1,2 ]}

ADVANCED MATERIALS, 2021, 33(4): 文献号: 2006483

DOI: 10.1002/adma.202006483

摘要

The imbalance of amyloid-beta (A beta) production and clearance causes aggregation of A beta(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, A beta(1-42) is the most important target for the treatment of AD. However, developing a single treatment method that can recognize A beta(1-42), inhibit A beta(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-A beta 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 A beta(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.