Stepwise Coordination-Driven Metal–Phenolic Nanoparticle as a Neuroprotection Enhancer for Alzheimer’s Disease Therapy

Abstract

Current therapeutic strategies for Alzheimer's disease (AD) mainly focus on inhibition of aberrant amyloid-β peptide (Aβ) aggregation. However, these strategies cannot repair the side symptoms (e.g., high neuronal oxidative stress) triggered by Aβ accumulation and thus show limited effects on suppressing Aβ-induced neuronal apoptosis. Herein, we develop a stepwise metal−phenolic coordination approach for the rational design of a neuroprotection enhancer, K8@Fe−Rh/Pda NPs, in which rhein and polydopamine are effectively coupled to enhance the treatment of AD in APPswe/PSEN1dE9 transgenic (APP/PS1) mice. We discover that the polydopamine inhibits the aggregation of Aβ oligomers, and rhein helps repair damage to neurons triggered by Aβ aggregation. Based on molecular docking, we demonstrate that the polydopamine has a strong interaction with Aβ monomers/ fibrils through its multiple recognition sites (e.g., catechol groups, imine groups, and indolic/catecholic π-systems), thereby reducing Aβ burden. Further investigation of the antioxidant mechanisms suggests that K8@Fe−Rh/Pda NPs promote the mitochondrial biogenesis via activating the sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha pathway. This finally inhibits neuronal apoptosis. Moreover, an intravenous injection of these nanoparticles potently improves the cognitive function in APP/PS1 mice without adverse effects. Overall, our work provides a promising approach to develop advanced nanomaterials for multi-target treatment of AD.

Design of aggregation-induced emission-active fluorogen-based nanoparticles for imaging and scavenging Alzheimer's β-amyloid by photo-oxygenation

“…The Ab fibril-targeting capability of a photo-oxidant is an essential factor for its inhibition and imaging. 49,54 55 The Ab plaques stained with ThT (green) and T-LD NPs (red) were located in the same region (Fig. 3), indicating that T-LD NPs could target Ab plaques.…”

“…The Aβ fibril-targeting capability of a photo-oxidant is an essential factor for its inhibition and imaging. 49,54 Therefore, the targeting capability of T NPs and T-LD NPs was investigated by confocal laser scanning microscopy (CLSM). As shown in Fig.…”

“…1A 46,47 Cell penetrating peptides (CPPs) have been used to enhance the BBB permeability of NPs reported in the literature. 48,49 Therefore, future research should direct toward enhancing the BBB permeability of the T-LD NPs by conjugating CPPs for in vivo studies.…”

Nanomedicines for Alzheimer's disease: Therapies based on pathological mechanisms

“…Reproduced from Ref. [85] with permission. (K) Neurons (SH-SY5Y cell line) were pretreated with 2 � 10 −6 m Aβ1-42 proteins in the absence or presence of extracellular vesicles (EVs) and EVs-SHP2 for 24 h. Colocalization between mitochondria (green, stained with MitoTracker) and lysosomes (eed, stained with LysoTracker) was observed (left).…”

“…Therefore, stimulating mitochondrial biogenesis is a promising approach for AD treatment. Gao's group attempted to activate mitochondrial biogenesis with a nanomedicine [85] . They loaded rhein into a K8‐targeting peptide‐modified nanocarrier.…”