Nanocomposites Inhibit the Formation, Mitigate the Neurotoxicity, and Facilitate the Removal of beta-Amyloid Aggregates in Alzheimer's Disease Mice

Zhao, Y (Zhao, Yu)^[ 1 ] ; Cai, JQ (Cai, Jinquan)^[ 6 ] ; Liu, ZC (Liu, Zichen)^[ 1 ] ; Li, YS (Li, Yansheng)^[ 3,4,5 ] ; Zheng, CX (Zheng, Chunxiong)^[ 1 ] ; Zheng, YD(Zheng, Yadan)^[ 1 ] ; Chen, Q (Chen, Qun)^[ 6 ] ; Chen, HY (Chen, Hongyun)^[ 7 ] ; Ma, FH (Ma, Feihe)^[ 1 ] ; An, YL (An, Yingli)^[ 1 ] ; Xiao, LH (Xiao, Lehui)^[ 2 ] ; Jiang, CL(Jiang, Chuanlu)^[ 6 ] ; Shi, LQ (Shi, Linqi)^[ 1 ] ; Kang, CS (Kang, Chunsheng)^[ 3,4,5 ] ; Liu, Y (Liu, Yang)^{[ 1,3,4,5 ]} ...

NANO LETTERS, 2019, 19(2): 674-683

DOI: 10.1021/acs.nanolett.8b03644

Abstract

Alzheimer's disease (AD) is a progressive and irreversible brain disorder. Recent studies revealed the pivotal role of beta-amyloid (A beta) in AD. However, there is no conclusive indication that the existing therapeutic strategies exerted any effect on the mitigation of A beta-induced neurotoxicity and the elimination of A beta aggregates simultaneously in vivo. Herein, we developed a novel nanocomposite that can eliminate toxic A beta aggregates and mitigate A beta-induced neurotoxicity in AD mice. This nanocomposite was designed to be a small-sized particle (14 +/- 4 nm) with A beta-binding peptides (KLVFF) integrated on the surface. The nanocomposite was prepared by wrapping a protein molecule with a cross-linked KLVFF-containing polymer layer synthesized by in situ polymerization. The presence of the nanocomposite remarkably changed the morphology of A beta aggregates, which led to the formation of A beta/nanocomposite coassembled nanoclusters instead of A beta oligomers. With the reduction of the pathological A beta oligomers, the nanocomposites attenuated the A beta-induced neuron damages, regained endocranial microglia's capability to phagocytose A beta, and eventually protected hippocampal neurons against apoptosis. Thus, we anticipate that the small-sized nanocomposite will potentially offer a feasible strategy in the development of novel AD treatments.