An "Amyloid-β Cleaner" for the Treatment of Alzheimer's Disease by Normalizing Microglial Dysfunction

Ruiyuan Liu; Jun Yang; Linying Liu; Zhiguo Lu; Zhuyan Shi; Weihong Ji; Jie Shen; Xin Zhang

doi:10.1002/advs.201901555

An "Amyloid-β Cleaner" for the Treatment of Alzheimer's Disease by Normalizing Microglial Dysfunction

Adv Sci (Weinh). 2019 Nov 22;7(2):1901555. doi: 10.1002/advs.201901555. eCollection 2020 Jan.

Authors

Ruiyuan Liu^{1

2}, Jun Yang¹, Linying Liu^{1

2}, Zhiguo Lu^{1

2}, Zhuyan Shi^{1

2}, Weihong Ji^{1

2}, Jie Shen^{1

2}, Xin Zhang¹

Affiliations

¹ State Key Laboratory of Biochemical Engineering Institute of Process Engineering Chinese Academy of Sciences Beijing 100190 P. R. China.
² School of Chemical Engineering University of Chinese Academy of Sciences Beijing 100049 P. R. China.

Abstract

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by progressive cognitive and memory loss. The vicious circle between dysfunctional microglia and amyloid-β (Aβ) is a crucial pathological event and accelerates the progression of AD. Herein, a zwitterionic poly(carboxybetaine) (PCB)-based nanoparticle (MCPZFS NP) with normalizing the dysfunctional microglia and Aβ recruitment is established for the treatment of AD. Compared with the neural polyethylene glycol (PEG)-based nanoparticles (MEPZFS NPs), the MCPZFS NPs significantly alleviate the priming of microglia by decreasing the level of proinflammatory mediators and promoting the secretion of BDNF. Most importantly, quite different from PEG, the PCB-based NPs exhibit the behavior to recruit Aβ into microglia, which significantly enhances the Aβ phagocytosis. Moreover, the Aβ degradation is changed from the conventional lysosomal/autophagy to the proteasomal pathway in the presence of MCPZFS NPs. After the treatment with MCPZFS NPs, the Aβ burden, neuron damages, memory deficits, and neuroinflammation of APPswe/PS1dE9 mice are significantly attenuated in the brain. Therefore, the PCB-based MCPZFS NPs have great potential to serve as an "Aβ cleaner" and provide a new insight into the therapeutic strategy for AD therapy.

Keywords: Alzheimer's disease; Aβ; microglia; neuroinflammation; phagocytosis.