Fluorescent Dopamine-Tryptophan Nanocomposites as Dual-Imaging and Antiaggregation Agents: New Generation of Amyloid Theranostics with Trimeric Effects.

Abstract

The aggregation of neurotoxic amyloid-β (Aβ) polypeptides into aberrant extracellular senile plaques is the major neuropathological hallmark of Alzheimer's disease (AD). Inhibiting aggregation of these peptides to control the progression of this deadly disease can serve as a viable therapeutic option. In the current work, inherently fluorescent theranostic dopamine-tryptophan nanocomposites (DTNPs) were developed and investigated for their amyloid inhibition propensity along with their ability to act as a cellular bioimaging agent in neuronal cells. The antiaggregation potency of the nanocomposites was further investigated against an in vitro established reductionist amyloid aggregation model consisting of a mere dipeptide, phenylalanine-phenylalanine (FF). As opposed to large peptide/protein-derived robust and high-molecular-weight amyloid aggregation models of Alzheimer's disease, our dipeptide-based amyloid model provides an edge over others in terms of the ease of handling, synthesis, and cost-effectiveness. Results demonstrated positive antiaggregation behavior of the DTNPs toward both FF-derived amyloid fibrils and preformed Aβ-peptide fibers by means of electron microscopic and circular dichroism-based studies. Our results further pointed toward the neuroprotective effects of the DTNPs in neuroblastoma cells against FF amyloid fibril-induced toxicity and also that they significantly suppressed the accumulation of Aβ42 oligomers in both cortex and hippocampus regions and improved cognitive impairment in an intracerebroventricular streptozotocin (ICV-STZ)-induced animal model of dementia. Besides, DTNPs also exhibited excellent fluorescent properties and light up the cytoplasm of neuroblastoma cells when being coincubated with cells, confirming their ability to serve as an intracellular bioimaging agent. Overall, these results signify the potency of the DTNPs as promising multifunctional theranostic agents for treating AD.