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Polyoxometalates as Effective Nano-inhibitors of Amyloid Aggregation of Pro-inflammatory S100A9 Protein Involved in Neurodegenerative Diseases

Chaudhary, Himanshu ; Iashchishyn, Igor A. ; Romanova, Nina V. ; Rambaran, Mark A. LU ; Musteikyte, Greta ; Smirnovas, Vytautas ; Holmboe, Michael ; Ohlin, C. André ; Svedružić, Željko M. and Morozova-Roche, Ludmilla A. (2021) In ACS Applied Materials and Interfaces 13(23). p.26721-26734
Abstract

Pro-inflammatory and amyloidogenic S100A9 protein is central to the amyloid-neuroinflammatory cascade in neurodegenerative diseases. Polyoxometalates (POMs) constitute a diverse group of nanomaterials, which showed potency in amyloid inhibition. Here, we have demonstrated that two selected nanosized niobium POMs, Nb10 and TiNb9, can act as potent inhibitors of S100A9 amyloid assembly. Kinetics analysis based on ThT fluorescence experiments showed that addition of either Nb10 or TiNb9 reduces the S100A9 amyloid formation rate and amyloid quantity. Atomic force microscopy imaging demonstrated the complete absence of long S100A9 amyloid fibrils at increasing concentrations of either POM and the presence of only round-shaped and slightly... (More)

Pro-inflammatory and amyloidogenic S100A9 protein is central to the amyloid-neuroinflammatory cascade in neurodegenerative diseases. Polyoxometalates (POMs) constitute a diverse group of nanomaterials, which showed potency in amyloid inhibition. Here, we have demonstrated that two selected nanosized niobium POMs, Nb10 and TiNb9, can act as potent inhibitors of S100A9 amyloid assembly. Kinetics analysis based on ThT fluorescence experiments showed that addition of either Nb10 or TiNb9 reduces the S100A9 amyloid formation rate and amyloid quantity. Atomic force microscopy imaging demonstrated the complete absence of long S100A9 amyloid fibrils at increasing concentrations of either POM and the presence of only round-shaped and slightly elongated aggregates. Molecular dynamics simulation revealed that both Nb10 and TiNb9 bind to native S100A9 homo-dimer by forming ionic interactions with the positively charged Lys residue-rich patches on the protein surface. The acrylamide quenching of intrinsic fluorescence showed that POM binding does not perturb the Trp 88 environment. The far and near UV circular dichroism revealed no large-scale perturbation of S100A9 secondary and tertiary structures upon POM binding. These indicate that POM binding involves only local conformational changes in the binding sites. By using intrinsic and 8-anilino-1-naphthalene sulfonate fluorescence titration experiments, we found that POMs bind to S100A9 with a Kd of ca. 2.5 μM. We suggest that the region, including Lys 50 to Lys 54 and characterized by high amyloid propensity, could be the key sequences involved in S1009 amyloid self-assembly. The inhibition and complete hindering of S100A9 amyloid pathways may be used in the therapeutic applications targeting the amyloid-neuroinflammatory cascade in neurodegenerative diseases.

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author
; ; ; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
amyloid, amyloid-neuroinflammatory cascade, decaniobate, fibrils, inhibition, polyoxometalate, S100A9, titanoniobate
in
ACS Applied Materials and Interfaces
volume
13
issue
23
pages
14 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • pmid:34080430
  • scopus:85108385742
ISSN
1944-8244
DOI
10.1021/acsami.1c04163
language
English
LU publication?
no
additional info
Publisher Copyright: © 2021 The Authors. Published by American Chemical Society.
id
bfc03a12-2c9d-481f-ac45-24eabeae6fbf
date added to LUP
2023-02-15 16:54:02
date last changed
2024-02-18 13:17:48
@article{bfc03a12-2c9d-481f-ac45-24eabeae6fbf,
  abstract     = {{<p>Pro-inflammatory and amyloidogenic S100A9 protein is central to the amyloid-neuroinflammatory cascade in neurodegenerative diseases. Polyoxometalates (POMs) constitute a diverse group of nanomaterials, which showed potency in amyloid inhibition. Here, we have demonstrated that two selected nanosized niobium POMs, Nb10 and TiNb9, can act as potent inhibitors of S100A9 amyloid assembly. Kinetics analysis based on ThT fluorescence experiments showed that addition of either Nb10 or TiNb9 reduces the S100A9 amyloid formation rate and amyloid quantity. Atomic force microscopy imaging demonstrated the complete absence of long S100A9 amyloid fibrils at increasing concentrations of either POM and the presence of only round-shaped and slightly elongated aggregates. Molecular dynamics simulation revealed that both Nb10 and TiNb9 bind to native S100A9 homo-dimer by forming ionic interactions with the positively charged Lys residue-rich patches on the protein surface. The acrylamide quenching of intrinsic fluorescence showed that POM binding does not perturb the Trp 88 environment. The far and near UV circular dichroism revealed no large-scale perturbation of S100A9 secondary and tertiary structures upon POM binding. These indicate that POM binding involves only local conformational changes in the binding sites. By using intrinsic and 8-anilino-1-naphthalene sulfonate fluorescence titration experiments, we found that POMs bind to S100A9 with a Kd of ca. 2.5 μM. We suggest that the region, including Lys 50 to Lys 54 and characterized by high amyloid propensity, could be the key sequences involved in S1009 amyloid self-assembly. The inhibition and complete hindering of S100A9 amyloid pathways may be used in the therapeutic applications targeting the amyloid-neuroinflammatory cascade in neurodegenerative diseases.</p>}},
  author       = {{Chaudhary, Himanshu and Iashchishyn, Igor A. and Romanova, Nina V. and Rambaran, Mark A. and Musteikyte, Greta and Smirnovas, Vytautas and Holmboe, Michael and Ohlin, C. André and Svedružić, Željko M. and Morozova-Roche, Ludmilla A.}},
  issn         = {{1944-8244}},
  keywords     = {{amyloid; amyloid-neuroinflammatory cascade; decaniobate; fibrils; inhibition; polyoxometalate; S100A9; titanoniobate}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{23}},
  pages        = {{26721--26734}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{ACS Applied Materials and Interfaces}},
  title        = {{Polyoxometalates as Effective Nano-inhibitors of Amyloid Aggregation of Pro-inflammatory S100A9 Protein Involved in Neurodegenerative Diseases}},
  url          = {{http://dx.doi.org/10.1021/acsami.1c04163}},
  doi          = {{10.1021/acsami.1c04163}},
  volume       = {{13}},
  year         = {{2021}},
}