Amyloid Targeting “Artificial Chaperone” Impairs Oligomer Mediated Neuronal Damage and Mitochondrial Dysfunction Associated with Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is an irreversible memory disorder associated with multiple neuropathological events including amyloid aggregation that triggers oxidative stress and mitochondrial dysfunction in humans. Herein, a new artificial chaperone, benzimidazole functionalized polyfluorene (PFBZ) is reported to efficiently sequester toxic amyloid beta (Aβ) by binding at their 'amyloidogenic domain' (Aβ16−21) with unprecedented selectivity and prevent amyloid-mediated neuronal damage in a wild-type (WT) mouse model. An accurate dose of PFBZ chaperone successfully attenuated an amyloid triggered internal hemorrhage and pyknosis in the cerebral cortex of WT mice. The structural advantage of the polymer results in an efficient Cu(II) chelation arresting a redox cycle to prevent reactive oxygen species (ROS) generation and protect mitochondria from ROS mediated damage. This was further evidenced by caspase activation and mitochondrial membrane potential (MMP) biomarkers and was complemented by brain histology and electron microscopy data which revealed that the PFBZ chaperone provided a protective coating over the amyloid surface and resists from interacting with cell membrane and prevents inducing toxicity. This conjugated polymer artificial chaperone-based nanodrug showed exceptional properties such as its multipotent and highly biocompatible nature, the first of its kind with specific amyloid (Aβ16−21) targeting behavior, bioimaging, and BBB permeability with a potential to suppress amyloid triggered neurotoxicity implicated in numerous human disorders through a rare synergistic mechanism.

Clinically oriented Alzheimer's biosensors: expanding the horizons towards point-of-care diagnostics and beyond

“…29 The origin of neurotoxicity in Ab ( 40) peptides relies on the Ab (residues [16][17][18][19][20][21]) which is the central hydrophobic segment for the amyloid brillization known as the "amyloidogenic domain". [41][42][43] CSF contains different types of Ab plaques, where the major compounds correspond to Ab (40) and Ab (42) isoforms. Other forms of peptides are also generated from APP in minor percentages.…”

Conjugated Polymer Nanoparticles as a Fluorescence Probe for Amplified Detection of Human Serum Bilirubin

“…Herein, we have designed a novel conjugated polymer nanoparticle PFBZ [poly1,1′-((2,7-dimethyl-9 H -fluorene-9,9-diyl)­bis­(hexane-6,1-diyl))­bis­(1H-benzo­[ d ]­imidazole)] with a specific receptor for the selective detection of BR. The pendant benzimidazole moiety strapped at the site chains of the PFBZ polymer nanoparticle imparts solubility in polar organic solvents and spontaneously form nanoparticles in aqueous media . The polymer nanoparticle exhibits ultrasensitivity toward BR with a detection limit in the picomolar range due to the combined effect of huge spectral overlap of polymer emission with BR absorption and ground state complexation.…”

“…The pendant benzimidazole moiety strapped at the site chains of the PFBZ polymer nanoparticle imparts solubility in polar organic solvents and spontaneously form nanoparticles in aqueous media. 33 The polymer nanoparticle exhibits ultrasensitivity toward BR with a detection limit in the picomolar range due to the combined effect of huge spectral overlap of polymer emission with BR absorption and ground state complexation. Low-cost, portable paper strips were fabricated to demonstrate the ability of PFBZ for real-time BR sensing, which is covered in this work for the first time.…”

Multifunctional Metal–Organic Framework as a Versatile Nanoplatform for Aβ Oligomer Imaging and Chemo-Photothermal Treatment in Living Cells

“…8,9 Persistent oxidative damages caused by Aβ itself, and the coordination with metal ions, which further produce ROS, forms a vicious cycle that exacerbate the progress of AD steeply. 10,11 In view of the critical role of AβO in AD and the earlier appearance of AβO in brains, 12,13 AβO has been considered a more appropriate and appealing biomarker for early AD studies. Therefore, it is urgent to design a promising therapeutic strategy that can target AβO for preventing or delaying the onset of AD.…”

“…It is accordingly recognized that the complexity of AD etiology is mainly mediated by a series of AβO-centered cascades, such as reactive oxidative species (ROS)-overproduction and synaptoxicity . AβO accumulation is able to induce overproduction of ROS, which has been identified as a key contributing factor in the progression of AD. , The overproduction of ROS causes mitochondrial dysfunction, reduces antioxidant defense, and alters cellular metabolism, which can directly alter neurotransmission and synaptic plasticity in the brain, leading to impairment of cognition. , Persistent oxidative damages caused by Aβ itself, and the coordination with metal ions, which further produce ROS, forms a vicious cycle that exacerbate the progress of AD steeply. , In view of the critical role of AβO in AD and the earlier appearance of AβO in brains, , AβO has been considered a more appropriate and appealing biomarker for early AD studies. Therefore, it is urgent to design a promising therapeutic strategy that can target AβO for preventing or delaying the onset of AD.…”