Heat Shock Protein Inspired Nanochaperones Restore Amyloid-beta Homeostasis for Preventative Therapy of Alzheimer's Disease

Yang, HR (Yang, Huiru)^{[ 1 ]} ; Li, XY (Li, Xinyu)^{[ 2 ]} ; Zhu, L (Zhu, Lin)^{[ 1 ]} ; Wu, XH (Wu, Xiaohui)^{[ 1 ]} ; Zhang, SZ (Zhang, Shaozhi)^{[ 2 ]} ; Huang, F (Huang, Fan)^{[ 3,4 ]} ; Feng, XZ (Feng, Xizeng)^{[ 2 ]} ; Shi, LQ (Shi, Linqi)^{[ 1 ]}

ADVANCED SCIENCE, 2019, 文献号: 1901844

DOI: 10.1002/advs.201901844

摘要

Amyloid beta (A beta) aggregation is generally believed as the crucial and primary cause of Alzheimer's disease (AD). However, current A beta-targeted therapeutic strategies show limited disease-modifying efficacy due to the irreversible damages in the late stage of AD, thus the treatment should be given before the formation of deposition and target primary A beta species rather than advanced plaques. Herein, inspired by heat shock protein, a self-assembly nanochaperone based on mixed-shell polymeric micelle (MSPM) is devised to act as a novel strategy for AD prevention. With unique surface hydrophobic domains, this nanochaperone can selectively capture A beta peptides, effectively suppress A beta aggregation, and remarkably reduce A beta-mediated cytotoxicity. Moreover, the formed nanochaperone-A beta complex after A beta adsorption can be easily phagocytosed by microglia and thereby facilitates A beta clearance. As a result, the nanochaperone reduces A beta burden, attenuates A beta-induced inflammation, and eventually rescues the cognitive deficits of APP/PS1 transgenic AD mice. These results indicate that this biomimetic nanochaperone can successfully prevent the onset of AD symptoms and serve as a promising candidate for prophylactic treatment of AD.