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, 7 (3), e32953

MRP14 (S100A9) Protein Interacts With Alzheimer Beta-Amyloid Peptide and Induces Its Fibrillization


MRP14 (S100A9) Protein Interacts With Alzheimer Beta-Amyloid Peptide and Induces Its Fibrillization

Ce Zhang et al. PLoS One.


Increasing evidence supports the contribution of local inflammation to the development of Alzheimer's disease (AD) pathology, although the precise mechanisms are not clear. In this study, we demonstrate that the pro-inflammatory protein S100A9 interacts with the Aβ1-40 peptide and promotes the formation of fibrillar β-amyloid structures. This interaction also results in reduced S100A9 cytotoxicity by the binding of S100A9 toxic species to Aβ1-40 amyloid structures. These results suggest that secretion of S100A9 during inflammation promotes the formation of amyloid plaques. By acting as a sink for toxic species, plaque formation may be the result of a protective response within the brain of AD patients, in part mediated by S100A9.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.


Figure 1
Figure 1. AFM images of freshly dissolved A1–40 peptide (0.2 mM) and S100A9 protein (0.02 mM) mixture,
incubated at pH 7.4 and 37formula imageC for (a) 1 d; and (b) 3 d. S100A9 (0.2 mM) with (c) Aformula image1–40 (0.1 mM) ; (d) Aformula image1–40 (0.02 mM) incubated at pH 7.4 and 37formula imageC for 3 d. The scale bars denote 1000 nm for Fig. (a), 1200 nm for (b), 600 nm for (c) and 600 nm for (d).
Figure 2
Figure 2. ThT and CD spectra of S100A9/A1–40 (0.2 mM) complex.
(a) Kinetics of S100A9/Aformula image1–40 mixture amyloid formation at pH 7.4 and 37formula imageC monitored by the thioflavin-T assay. Rhombuses correspond to 0.2 mM Aformula image1–40. Squares correspond to 0.2 mM S100A9 and 0.1 mM Aformula image1–40. Circles correspond to 0.02 mM S100A9 and 0.2 mM Aformula image1–40 (b) CD spectra of Aformula image1–40 peptide (0.2 mM), S100A9 (0.02 mM) and their mixture, incubated at pH 7.4 and 37formula imageC for 1 d.
Figure 3
Figure 3. Difference CD spectra of S100A9 (0.2 mM) with the addition of various concentrations A1–40 peptide (0.002 mM to 0.1 mM)
incubated at pH 7.4 and 37formula imageC for (a) 3 d; (b) 7 d. The difference CD spectra are obtained by subtracting the ellipticity of the mixture with the ones containing only S100A9 (0.2 mM). (c) Ellipticity of S100A9 (0.2 mM) and Aformula image1–40 (0.2 mM) mixture during 9 d of incubation at pH 7.4 and 37formula imageC. (d) Detailed features of panel c.
Figure 4
Figure 4. Measurements of NHSY5Y cell line viability by WST1 assay in the presence of 0.02 mM S100A9 and various S100A9/A1–40 mixtures.
The S100A9 concentration remained 0.02 mM. The concentration of Aformula image1–40 addition varied from 0.02 mM to 0.4 mM. In control experiments, the cells were incubated in DMEM cell culture buffer alone and the cell viability was equal to 100%.
Figure 5
Figure 5. Electrophoresis of S100A9 incubated with NHSY5Y cells.
(a) and (c) SDS PAGE; (b) Native PAGE. Panel (a) has the following designations: column 1 corresponds to the ladder; 2 to S100A9 (0.2 mM); 3 to cell culture buffer DMEM; 4 to S100A9 (0.04 mM) with cells in DMEM for 3 d; 5 to S100A9 (0.01 mM) with cells in DMEM. In panel (b), 1 to S100A9 (0.2 mM); 2 to DMEM; 3 to S100A9 (0.04 mM) with cells in DMEM for 3 d. (c) 0.2 mM S100A9 at pH 3.0 and 7.4. The data was obtained by several experiments, and integrated together according to the ladders.
Figure 6
Figure 6. Electrophoresis and gas-phase electrophoretic mobility molecular analysis (GEMMA) of S100A9 and S100A9/A1–40 mixture.
(a) SDS PAGE of S100A9 with (1) 0.002 mM; (2) 0.01 mM; (3) 0.02 mM; (4) 0.1 mM Aformula image1–40 and native PAGE of (5) 0.2 mM S100A9 with 0.01 mM Aformula image1–40; (6) 0.2 mM S100A9 with 0.1 mM Aformula image1–40; (7) 0.1 mM Aformula image1–40; (8) 0.01 mM Aformula image1–40. The final concentration of S100A9 is 0.2 mM. The data was obtained by several experiments, and integrated together according to the ladders. (b) Size distribution of S100A9 monomer and dimer at pH 7.4 and 3.0 examined by gas-phase electrophoretic mobility molecular analysis (GEMMA). The red columns represent S100A9 at pH 7.4. The blue ones represent S100A9 at pH3.0.
Figure 7
Figure 7. Amino acid sequence alignment of S100A9 in the hinge region and A12–24 peptide.
The hydrophobic cores of both proteins are marked in red. The charged residues are indicated with their approximate charges. All sequences were obtained from the SWISS-PORT protein database [26].

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