SARS-CoV-2 accelerates and exacerbates host amyloidogenesis

SARS-CoV-2 amyloidogenic componentsStudy typeObserved effectsRef.
Spike 1058 fragment (1058HGVVFLHVTYV1068)All-atom discrete molecular dynamics (DMD) simulationsSpike 1058 accelerated amyloid-beta (Aβ)42 cytotoxicity, aggregation, and fibrillization in vitro[136]
Spike532 (532NLVKNKCVNFNFNGLTGTGV551)
Spike601 (601GTNTSNQVAVLYQDVNCTEV620)		In vitro conversion assaySpike532 and 601 selectively seed and accelerate amyloid fibril formation of human prion protein and Aβ1–42, respectively[137]
Synthetic spike (S) protein peptidesIn vitroEndoproteolysis of S protein by the neutrophil elastase protease produced amyloidogenic peptides. Whereas full-length folded S-protein did not form amyloid fibrils[138]
S protein receptor binding domain (RBD) of the Alpha and Omicron variantsMolecular dynamics simulationAβ42 amyloid fibrils can bind to the RBDs of the S proteins and diffusively slide on the RBD surfaces[139]
S RBD of the Delta Plus and Omicron variantsIn vitro, in silico/experimental analysisThe RBD self-assembles into aggregates with 48.4% β-sheet content. The Omicron variety displays higher amyloidogenic potential due to distinct mutations in the RBD regions[140]
S protein 1 (S1)In vivo male Sprague-Dawley rat (6 weeks old) modelIn the rat brain, a single intranasal dose of S1 (0.5 μg/10 μL) doubled the aggregation of α-synuclein (α-syn) relative to controls[141]
Recombinant SARS-CoV-2 S1, S2, RBD, and nucleocapsid (N) proteins (NCAPs)In vitro, Escherichia coli, human embryonic kidney (HEK) Expi293F cell line, and other eukaryotic cell culturesRecombinant S1, S2, RBD, and NCAPs spontaneously self-assemble into nanoparticles/nanofibers forming amyloid-like structures in tested cell lines[142]
S proteins and NCAPsIn vitro HEK293 cells, bioinformatics analysisS proteins and NCAPs displayed high binding affinity with α-syn. The direct interactions elevated α-syn expression and accelerated aggregation, forming Lewy-like bodies in HEK293 cells[143]
NCAP low complexity domain (LCD)In vitroThe LCD of NCAP phase separates and forms amyloid-like structures in the presence of RNA[144]
NCAP, S proteinIn vitro, neuroblastoma SH-SY5Y cellsNCAP accelerated the aggregation of α-syn into amyloid fibrils via nucleation of multiple protein complexes. Whereas S protein had no effect on α-syn aggregation[145]
Envelope (E) protein C-terminus-derived 54SFYVYSRVK62 (SK9) peptideIn vitroSK9 not only self-assembles into amyloid fibrils, but also binds to amyloidogenic hotspots in lipid-free serum amyloid A (SAA), promoting SAA fibrillization[146]
E protein SK9 peptide (C-terminus)Molecular dynamics simulationThe binding of SK9 to SAA promotes amyloidosis by increasing the frequency and stability of amyloid fibrils to favor β-strand formation[147]
Open reading frame 6 (ORF6)High-speed atomic force microscopy visualizationORF6 amyloidogenic peptides spontaneously self-assemble into amyloid protofilaments[148]
ORF 6, ORF10In vitro, atomic force microscopy, transmission electron microscopy, amyloid prediction algorithmsORF6 and ORF10 peptide sequences self-assemble into ground state amyloid crystals markedly elevated the rate of apoptosis at low concentrations in a human-derived neuroblastoma cell line (SH-SY5Y)[149]
S protein fusion peptide 1, 2, ORF10, non-structural protein 6 (NSP6), NSP11In vitro aggregation studyAll structural, accessory, and NSPs studied form amyloid aggregates with high propensity under near-physiological in vitro conditions[150]
NSP3Transgenic Alzheimer’s disease (AD) Drosophila melanogaster eye model [glass multiple repeats (GMR) > Aβ42]NSP3 misexpression in AD fly eye worsens Aβ42-mediated neurodegeneration, increases apoptotic cell death and ROS[151]
UV-inactivated SARS-CoV-2 virusEx vivo, healthy human cerebrospinal fluid (CSF)UV-inactivated nucleic acids act as catalysts promoting amyloid aggregation and markedly depleting soluble proteins in human CSF compared to controls[152]
SARS-CoV-2 S proteinTransnasal infection of 18hACE2 miceIncreased accumulation of phosphorylated tau protein and activation of glycogen synthase kinase 3β in the ventral tegmental region induced neuronal cell death[153]