Template-Mediated Detoxification of Low-Molecular-Weight Amyloid Oligomers and Regulation of Their Nucleation Pathway

Abstract

Amyloid tetramer, the most toxic low-molecular-weight (LMW) amyloid oligomer, leads to synaptic dysfunction and plays a vital role in pathophysiology of Alzheimer’s disease (AD). Hence, their kinetic inhibition may be regarded as a potential therapeutic strategy against AD. However, because of their dynamic, metastable nature, not much information has been gathered about them. Herein, amyloid tetramers have been isolated from a mixture pool of low- and high-molecular-weight amyloid oligomers. Kinetics of such tetrameric species has been studied in an in vitro model and inhibition of the fibrillation of the species has been achieved by means of a novel isatin functionalized polyfluorene derivative (PFIS). Isatin interacts with tetramers noncovalently to modulate its fibrillation by forming stable polymer–peptide coaggregates. In parallel to this, hydrophobic PFIS forms spherical nanoparticle in water that provides an external surface, which functions to modulate nucleation pathway of the oligomers. The polymer–peptide coaggregates are nontoxic in nature. Hence, these observations offer a potential strategy to suppress neurotoxicity of a LMW oligomer by forming nontoxic coaggregates. In parallel to this, our methodology also provides a potential strategy to observe and regulate nucleation pathway of the oligomers as well.

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

“…Benzimidazole functionalized polyfluorene (PFBZ) chaperone was synthesized by modifying an established protocol (Figure S7). , Briefly, fluorene was reacted with 1,6-dibromohexane in the presence of 50% aqueous NaOH (Figure S8). The organic part was extracted, purified by column chromatography, and subjected to oxidative polymerization to obtain polymer (PFBr) (Figure S9).…”

“…Therefore, due to the multiple factors involved in the AD etiology, a specific multi-targeted therapeutic strategy has to be adopted that can inhibit Aβ oligomerization and mitigate neuronal damage caused by multiple factors including mitochondrial dysfunctions, ROS production, caspase-3 activation, and many more. In the past few decades, therapeutic materials solely targeting Aβ have been developed. − However, most of those single targeted drugs have proven to be inadequate and failed during different stages of clinical trials, suggesting a multi-targeted drug approach to address multifactorial toxicity involved in AD to be the best option. , These limitations in single targeted drugs prompted us to systematically investigate the various biochemical events triggered by Aβ40 oligomers, leading ultimately to mitochondrial dysfunction and neuronal damage in wild-type (WT) mice. We also report for the first time the specific design of an amyloid targeting polymeric chaperone, benzimidazole functionalized polyfluorene (PFBZ) that can mitigate Aβ triggered neurotoxicity through regulation of ROS production, caspase activation, and mitochondrial dysfunction (Scheme ).…”

Amyloid Targeting Red Emitting AIE Dots for Diagnostic and Therapeutic Application against Alzheimer’s Disease

“…23 A unique low molecular weight (LMW) oligomer was extracted from a pool of oligomeric mixture, their inherent kinetics were investigated, and their interaction with a smart probe was analyzed. 24 The small molecule probe binds to oligomeric species, producing a spherical coaggregate and preventing further proliferation. Amyloid nucleation occurs via the primary pathway, but in the presence of the TPA-BTZ probe, nucleation occurs via the secondary pathway.…”

Self-Assembly Driven Formation of Functional Ultralong “Artificial Fibers” to Mitigate the Neuronal Damage Associated with Alzheimer’s Disease

“…A recent report reveals that PARP induces mitochondrial apoptosis by releasing the apoptosis-inducing factor (AIF) to cause depolarization in mitochondrial membrane potential (MMP). Several therapeutic materials including peptides, engineered nanoparticles, functionalized polymers, and most recently monoclonal antibodies have exhibited appreciable degree of anti-Alzheimer’s activities. – However, most of these amyloid-targeting therapeutic material have proven to be inefficient and failed in the different phases of clinical trial. , One plausible reason behind such failure may be the involvement of the multidimensional toxicity associated with AD that includes oxidative stress, PARP cleavage, caspase activation, and mitochondrial dysfunction. Herein, an amyloid-targeting molecule (INHQ) that spontaneously self-assembles into ultralong fibers and shows striking resemblance with the amyloid morphology has been developed.…”