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

Abstract

Fibrillation of amyloid beta (Aβ) is the key event in the amyloid neurotoxicity process that induces a chain of toxic events including oxidative stress, caspase activation, poly­(ADP-ribose) polymerase cleavage, and mitochondrial dysfunction resulting in neuronal loss and memory decline manifesting as clinical dementia in humans. Herein, we report the development of a novel, biologically active supramolecular probe, INHQ, and achieve functional nanoarchitectures via a self-assembly process such that ultralong fibers are achieved spontaneously. With specifically decorated functional groups on INHQ such as imidazole, hydroxyquinoline, hydrophobic chain, and hydroxyquinoline molecules, these ultralong fibers coassembled efficiently with toxic Aβ oligomers and mitigated the amyloid-induced neurotoxicity by blocking the aforementioned biochemical events leading to neuronal damage in mice. These functional ultralong “Artificial Fibers” morphologically resemble the amyloid fibers and provide a higher surface area of interaction that improves its clearance ability against the Aβ aggregates. The efficacy of this novel INHQ molecule was ascertained by its high ability to interact with Aβ. Moreover, this injectable, ultralong INHQ functional “artificial fiber” translocates through the blood–brain barrier and successfully attenuates the amyloid-triggered neuronal damage and pyknosis in the cerebral cortex of wild-type mouse. Utilizing various spectroscopic techniques, morphology analysis, and in vitro, in silico, and in vivo studies, these ultralong INHQ fibers are proven to hold great promise for treating neurological disorders at all stages with a potential to replace the existing medications, reduce complications in the brain, and eradicate the amyloid-triggered neurotoxicity implicated in numerous disorders in human through a rare synergistic mechanism.

Conjugated Polyelectrolytes: Illuminating the Path to Neurodegenerative Disorders Detection and Treatment

“…Aβ exhibits a notable affinity toward iron and copper, leading to the production of hydrogen peroxide, which is known to have neurotoxic properties. This interaction also induces oxidative stress and triggers the production of free radicals. , Heme has a critical role in regulating gene expression, facilitating cellular metabolic processes, and influencing toxicity levels. The brains of individuals diagnosed with AD have demonstrated a significant rise in heme b levels, with an observed increase of up to 250%.…”

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

“…Furthermore, TPA-BTZ has been demonstrated to engage with fibrillar species and cover their surfaces, preventing them from interacting with free monomers and disrupting the catalytic cycle that leads to additional oligomer formation. Cu helps to accelerate Aβ40 aggregation and causes an overabundance of ROS in the brain, which is linked to oxidative stress in neuronal cells and results in neuronal death. ,, Aβ interaction starts a pathological cascade that causes mitochondrial dysfunction. , The neurotoxicity of the small molecule smart probe has been studied. MTT assay was performed on SH-SY-5Y cell lines and found to be nontoxic.…”