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.…”

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.…”

Rhein Inhibits Microglia-Mediated Neuroinflammation and Neuronal Damage of Alzheimer’s Disease via Regulating the Glutamine–Aspartate–Arginine–NO Metabolic Pathway

“…The Morris water maze test was used to evaluate the learning and memory ability of rats. All rats were trained and tested in a circular pool with a diameter of 121 cm, as described earlier [ 45 ]. During the 4 days of training, each rat was placed into the pool from different positions around the border of the pool and swam for 60 s. If the rat failed to find the platform within 60 s, they were guided to the platform to stay for 15 s, and the escape latency was recorded as 60 s. At 24 h after the last training trial, the platform was removed, and the rats were tested for memory retention in a probe trial.…”

Neuronal Membrane-Coated Mesoporous Ceria Nanoparticles for Blood–Brain Barrier Crossing and Mitigation of Neurodegeneration

“…The effect of the developed bioinspired formulation on intracellular oxidative stress was evaluated in vitro on primary astrocytes by quantifying Reactive Oxygen Species (ROS) through a flow cytometer. 44 Briefly, cells were seeded at a density of 3 × 10 5 and cultured for 24 h at 37 °C in a controlled atmosphere. Subsequently, the cells were treated with MCN-10, MM, MCN-MM, and NM@MCN-MM.…”

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.…”

Rhein Inhibits Microglia-Mediated Neuroinflammation and Neuronal Damage of Alzheimer’s Disease via Regulating the Glutamine–Aspartate–Arginine–NO Metabolic Pathway

“…The Morris water maze test was used to evaluate the learning and memory ability of rats. All rats were trained and tested in a circular pool with a diameter of 121 cm, as described earlier [ 45 ]. During the 4 days of training, each rat was placed into the pool from different positions around the border of the pool and swam for 60 s. If the rat failed to find the platform within 60 s, they were guided to the platform to stay for 15 s, and the escape latency was recorded as 60 s. At 24 h after the last training trial, the platform was removed, and the rats were tested for memory retention in a probe trial.…”

Neuronal Membrane-Coated Mesoporous Ceria Nanoparticles for Blood–Brain Barrier Crossing and Mitigation of Neurodegeneration

“…The effect of the developed bioinspired formulation on intracellular oxidative stress was evaluated in vitro on primary astrocytes by quantifying Reactive Oxygen Species (ROS) through a flow cytometer. 44 Briefly, cells were seeded at a density of 3 × 10 5 and cultured for 24 h at 37 °C in a controlled atmosphere. Subsequently, the cells were treated with MCN-10, MM, MCN-MM, and NM@MCN-MM.…”

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.…”

Rhein Inhibits Microglia-Mediated Neuroinflammation and Neuronal Damage of Alzheimer’s Disease via Regulating the Glutamine–Aspartate–Arginine–NO Metabolic Pathway

“…The Morris water maze test was used to evaluate the learning and memory ability of rats. All rats were trained and tested in a circular pool with a diameter of 121 cm, as described earlier [ 45 ]. During the 4 days of training, each rat was placed into the pool from different positions around the border of the pool and swam for 60 s. If the rat failed to find the platform within 60 s, they were guided to the platform to stay for 15 s, and the escape latency was recorded as 60 s. At 24 h after the last training trial, the platform was removed, and the rats were tested for memory retention in a probe trial.…”

Neuronal Membrane-Coated Mesoporous Ceria Nanoparticles for Blood–Brain Barrier Crossing and Mitigation of Neurodegeneration

“…The effect of the developed bioinspired formulation on intracellular oxidative stress was evaluated in vitro on primary astrocytes by quantifying Reactive Oxygen Species (ROS) through a flow cytometer. 44 Briefly, cells were seeded at a density of 3 × 10 5 and cultured for 24 h at 37 °C in a controlled atmosphere. Subsequently, the cells were treated with MCN-10, MM, MCN-MM, and NM@MCN-MM.…”