An ATR–FTIR Sensor Unraveling the Drug Intervention of Methylene Blue, Congo Red, and Berberine on Human Tau and Aβ

Abstract

Alzheimer's disease affects millions of human beings worldwide. The disease progression is characterized by the formation of plaques and neurofibrillary tangles in the brain, which are based on aggregation processes of the Aβ peptide and tau protein. Today there is no cure and even no assay available for the identification of drug candidates, which provides direct information concerning the protein secondary structure label-free. Therefore, we developed an attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) sensor, which uses surface bound antibodies to immobilize a desired target protein. The secondary structure of the protein can be evaluated based on the secondary structure sensitive frequency of the amide I band. Direct information about the effect of a drug candidate on the secondary structure distribution of the total target protein fraction within the respective body fluid can be detected by a frequency shift of the amide I band. Thereby, the extent of the amide I shift is indicative for the compound efficiency. The functionality of this approach was demonstrated by the quantification of the effect of the drug candidate methylene blue on the pathogenic misfolded tau protein as extracted from cerebrospinal fluid (CSF). Methylene blue induces a shift from pathogenic folded β-sheet dominated to the healthy monomeric state. A similar effect was observed for congo red on pathogenic Aβ isoforms from CSF. In addition, the effect of berberine on synthetic Aβ is studied. Berberine seems to decelerate the aggregation process of synthetic Aβ peptides.

Amyloid-β misfolding as a plasma biomarker indicates risk for future clinical Alzheimer’s disease in individuals with subjective cognitive decline

“…Aβ misfolding can be monitored using an immuno-infrared sensor (iRS), which measures the frequency of the C=O stretching vibration of the Aβ backbone [ 23 , 34 ]. This vibration causes the amide I absorbance band, which in turn gives information about the secondary structure distribution of all Aβ isoforms [ 23 ].…”

The Effect of (−)-Epigallocatechin-3-Gallate on the Amyloid-β Secondary Structure

“…All antibodies were obtained from NanoTools (Teningen, Germany). Functionalization of the activated sensor surface followed the procedures reported in our previous work (30)(31)(32)(33).…”

“…The measurements are performed using the immunoinfrared sensor based on attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) technique. That sensor can monitor the effects of therapeutic molecules on disease-related biomarkers in a label-free manner as shown for methylene blue, Congo red, and berberine on Ab and t from human body fluids in real time under physiological conditions (30)(31)(32)(33). We then investigate the interactions between the Ab fibril model and EGCG using docking calculations, followed by MD simulations of the docked complex.…”

Grafting of Oligo(ethylene glycol)-Functionalized Calix[4]arene-Tetradiazonium Salts for Antifouling Germanium and Gold Surfaces

“…Ge has the advantages over Si (a much more studied element 12 ) to have a larger refractive index (resulting in a better signal-to-noise ratio) and to be transparent in a broader spectral range, allowing the study of more important chemical groups absorbing between 1400 and 800 cm −1 . Chemisorbed thiols 6,13 and silane derivatives 5,8,14,15 are generally used for the chemical modification of Ge surfaces. However, the lack of reproducible grafting protocols and lack of long-term stability in aqueous media of the obtained monolayers are important limitations of these methods.…”