ABSTRACT
Various oligomeric species of amyloid-beta have been proposed to play different immunogenic roles in the cellular pathology of Alzheimer's Disease. However, investigating the role of a homogenous single oligomeric species has been difficult due to highly dynamic oligomerization and fibril formation kinetics that convert between many species. Here we report the design and construction of a quantum dot mimetic for larger spherical oligomeric amyloid species as an "endogenously" fluorescent proxy for this cytotoxic species to investigate its role in inducing inflammatory and stress response states in neuronal and glial cell types.
ABSTRACT
Despite limited evidence for infection of SARS-CoV-2 in the central nervous system, cognitive impairment is a common complication reported in "recovered" COVID-19 patients. Identification of the origins of these neurological impairments is essential to inform therapeutic designs against them. However, such studies are limited, in part, by the current status of high-fidelity probes to visually investigate the effects of SARS-CoV-2 on the system of blood vessels and nerve cells in the brain, called the neurovascular unit. Here, we report that nanocrystal quantum dot micelles decorated with spike protein (COVID-QDs) are able to interrogate neurological damage due to SARS-CoV-2. In a transwell co-culture model of the neurovascular unit, exposure of brain endothelial cells to COVID-QDs elicited an inflammatory response in neurons and astrocytes without direct interaction with the COVID-QDs. These results provide compelling evidence of an inflammatory response without direct exposure to SARS-CoV-2-like nanoparticles. Additionally, we found that pretreatment with a neuro-protective molecule prevented endothelial cell damage resulting in substantial neurological protection. These results will accelerate studies into the mechanisms by which SARS-CoV-2 mediates neurologic dysfunction.
ABSTRACT
Amphipathic peptides with amino acids arranged in alternating patterns of hydrophobic and hydrophilic residues efficiently self-assemble into ß-sheet bilayer nanoribbons. Hydrophobic side chain functionality is effectively buried in the interior of the putative bilayer of these nanoribbons. This study investigates consequences on self-assembly of increasing the surface area of aromatic side chain groups that reside in the hydrophobic core of nanoribbons derived from Ac-(XKXE)2 -NH2 peptides (X = hydrophobic residue). A series of Ac-(XKXE)2 -NH2 peptides incorporating aromatic amino acids of increasing molecular volume and steric profile (X = phenylalanine [Phe], homophenylalanine [Hph], tryptophan [Trp], 1-naphthylalanine [1-Nal], 2-naphthylalanine [2-Nal], or biphenylalanine [Bip]) were assessed to determine substitution effects on self-assembly propensity and on morphology of the resulting nanoribbon structures. Additional studies were conducted to determine the effects of incorporating amino acids of differing steric profile in the hydrophobic core (Ac-X1 KFEFKFE-NH2 and Ac-(X1,5 KFE)-NH2 peptides, X = Trp or Bip). Spectroscopic analysis by circular dichroism (CD) and Fourier transform infrared (FT-IR) spectroscopy indicated ß-sheet formation for all variants. Self-assembly rate increased with peptide hydrophobicity; increased molecular volume of the hydrophobic side chain groups did not appear to induce kinetic penalties on self-assembly rates. Transmission electron microscopy (TEM) imaging indicated variation in fibril morphology as a function of amino acid in the X positions. This study confirms that hydrophobicity of amphipathic Ac-(XKXE)2 -NH2 peptides correlates to self-assembly propensity and that the hydrophobic core of the resulting nanoribbon bilayers has a significant capacity to accommodate sterically demanding functional groups. These findings provide insight that may be used to guide the exploitation of self-assembled amphipathic peptides as functional biomaterials.
