Peptide nanostructures block amyloid buildup and enhance neuronal survival in laboratory tests

Peptide nanostructures block amyloid buildup and enhance neuronal survival in laboratory tests

Scientists unveil a novel supramolecular therapy that protects human neurons from amyloid-induced damage and offers new hope for the treatment of Alzheimer's and related neurodegenerative diseases.

A recently published study in theJournal of the American Chemical SocietyExamines the role of biocompatible peptide amphiphiles in preventing the misfolding and aggregation of proteins associated with neurodegeneration.

Important pathological features of neurodegenerative diseases

Neurodegenerative diseases (NDs) are characterized by the death of neurons, leading to severe motor and cognitive impairments. The prevalence of NDs, including Parkinson's disease (PD), Alzheimer's disease (AD), and dementia, continues to rise worldwide, thereby increasing the burden on global health systems.

Protein aggregation such as amyloid beta (Aβ) and tau is characteristic of AD, while alpha-synuclein aggregation occurs in PD. Protein aggregation leads to the formation of amyloid protofilaments, which combine into amyloid fibrils that terminate at various locations within the cell.

Current treatment strategies for NDs include inhibiting protein aggregate formation, eliminating misfolded proteins, and modifying cellular responses to treat concurrent damage such as oxidative stress.

Innovative approaches to treating NDs

Previous studies have reported the therapeutic benefits of supramolecular self-assembly of materials, particularly nanomaterials, through noncovalent interactions. Peptide-based supramolecular materials are also associated with several advantageous properties for biomedical applications, including superior biocompatibility, bioavailability, and modularity compared to traditional peptides and proteins.

Structural units such as amino acid sequence or the assembly environment of peptide amphiphiles (PAS) can be modified to change the strength of their hydrogen bonds and various morphological features. Previously, researchers reported the copolymerization capacity of PA nanofibers with various soluble peptide sequences to form a metastable supramolecular assembly, which could improve the delivery of therapeutic peptides to rescue Aβ-related neurotoxicity.

Trehalose, a nonreducing, uncharged disaccharide, has recently been studied as a protein chaperone that can protect proteins from misfolding, denaturation, and aggregation. Trehalose also activates autophagy and reduces the accumulation of protein aggregates, thereby improving neurotoxicity.

About the study

The current study investigates the potential neuroprotective effects of trehalose-PA (TPA) in rescuing amyloid-related neurodegeneration. The researchers hypothesized that functionalization with trehalose would allow TPAs ​​to inhibit amyloid aggregation and stabilize the phenotypes of neurons affected by amyloid-related neurotoxicity.

Various computational methods were used to study interactions between unfunctionalized PAs and amyloid beta-1-42 peptide (Aβ42) to elucidate their ability to prevent amyloid aggregation. The therapeutic potential of TPAs ​​was further evaluatedin vitroUsing neurons derived from human induced pluripotent stem cells (IPSCs) to determine their effectiveness in protecting cells from Aβ42-induced neurotoxicity.

Therapeutic activity of PAs against neurodegenerative diseases

Palmitoyl-vvaaee (E2) was selected as the untalized backbone PA due to its superior biocompatibility and ability to present bioactive motifs with optimized density for neuronal application. TPAs were synthesized by conjugating and then functionalizing a lysine residue at the C-terminus of E2.

Small-angle synchrotron X-ray scattering (SAXS) was used to analyze E2 and TPA assemblies under annealed and uneasted conditions. E2 formed filamentous nanostructures under both conditions, while untested TPA formed nanofibers and TEMEAL TPA formed small micellar aggregates. The width of TPA nanofibers was smaller than that of E2 nanofibers.

Circular dichroism (CD) spectroscopy, solution synchrotron wide-angle X-ray scattering (WAXS) and Fourier transform infrared spectroscopy (FT-IR) analyzes showed a higher degree of decotonation of the glutamic acid residues in TPA assemblies. Cryogenic transmission electron microscopy (cryo-TEM) and negative staining TEM confirmed the spectroscopic results, indicating that both E2 formed twisted nanofibers with or without annealing.

VT (variable temperature) experiments showed that the melting point of the E2 assemblies was above 80 °C. Further heating to 90 °C caused the β-sheet signature of E2 to disappear.

The TPA assembly was stable at 50 °C, with its β-sheet signature shrinking at 65 °C, suggesting that TPA filamentous assemblies are metastable kinetic supramolecular structures at low temperatures. Furthermore, TPA supramolecular assemblies were found to alter the aggregation of Aβ42 and TPA-Aβ42 interactions, which altered the morphology of the nanostructure.

Human motor neurons (MNS) remained viable after treatment with 30 μm or less TPA. The monomeric Aβ42 was incubated at 37 °C for 16 h to induce Aβ42 toxicity, with four experimental TPA arrangements reducing cell death, indicating different levels of rescue. Notably, untreated TPA achieved the most effective rescue by reducing Aβ42 neurotoxicity.

Supramolecular nanostructures are an interesting target for therapeutic strategies in neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis. “

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