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

Abstract

Alzheimer's disease (AD) is a progressive and irreversible brain disorder. Recent studies revealed the pivotal role of β-amyloid (Aβ) in AD. However, there is no conclusive indication that the existing therapeutic strategies exerted any effect on the mitigation of Aβ-induced neurotoxicity and the elimination of Aβ aggregates simultaneously in vivo. Herein, we developed a novel nanocomposite that can eliminate toxic Aβ aggregates and mitigate Aβ-induced neurotoxicity in AD mice. This nanocomposite was designed to be a small-sized particle (14 ± 4 nm) with Aβ-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 Aβ aggregates, which led to the formation of Aβ/nanocomposite coassembled nanoclusters instead of Aβ oligomers. With the reduction of the pathological Aβ oligomers, the nanocomposites attenuated the Aβ-induced neuron damages, regained endocranial microglia's capability to phagocytose Aβ, 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.