The role of pro-inflammatory S100A9 in Alzheimer’s disease amyloid-neuroinflammatory cascade

Abstract

Pro-inflammatory S100A9 protein is increasingly recognized as an important contributor to inflammation-related neurodegeneration. Here, we provide insights into S100A9 specific mechanisms of action in Alzheimer’s disease (AD). Due to its inherent amyloidogenicity S100A9 contributes to amyloid plaque formation together with Aβ. In traumatic brain injury (TBI) S100A9 itself rapidly forms amyloid plaques, which were reactive with oligomer-specific antibodies, but not with Aβ and amyloid fibrillar antibodies. They may serve as precursor-plaques for AD, implicating TBI as an AD risk factor. S100A9 was observed in some hippocampal and cortical neurons in TBI, AD and non-demented aging. In vitro S100A9 forms neurotoxic linear and annular amyloids resembling Aβ protofilaments. S100A9 amyloid cytotoxicity and native S100A9 pro-inflammatory signaling can be mitigated by its co-aggregation with Aβ, which results in a variety of micron-scale amyloid complexes. NMR and molecular docking demonstrated transient interactions between native S100A9 and Aβ. Thus, abundantly present in AD brain pro-inflammatory S100A9, possessing also intrinsic amyloidogenic properties and ability to modulate Aβ aggregation, can serve as a link between the AD amyloid and neuroinflammatory cascades and as a prospective therapeutic target.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-013-1208-4) contains supplementary material, which is available to authorized users.

Retracted: S100A9 gene silencing inhibits the release of pro‐inflammatory cytokines by blocking the IL‐17 signalling pathway in mice with acute pancreatitis

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β-Hydroxybutyrate Deactivates Neutrophil NLRP3 Inflammasome to Relieve Gout Flares

“…S100A8/9 proteins are also reported to increase during age-related inflammatory diseases including obesity (Nagareddy et al, 2014), cardiovascular disease (Ma et al, 2012), Alzheimer’s disease (Wang et al, 2014), and in the aged prostate (Yanamandra et al, 2009). This implies these proteins may provide an endogenous, local signal 1 for NLRP3 inflammasome activation and may be universal biomarkers of inflammation (Vogl et al, 2007).…”

The Amyloid‐β Peptide in Amyloid Formation Processes: Interactions with Blood Proteins and Naturally Occurring Metal Ions

“…While S100A9 is not a very abundant blood protein, it is an amyloidogenic protein in itself that is strongly expressed during inflammation including inflammation‐associated AD . In vitro S100A9 and Aβ interact and seem to act as synergistic partners in amyloid formation . Like with fibrinogen, any role of S100A9 in the AD process is unclear, but the focus is again turned towards inflammatory brain processes affecting the AD progression.…”

“…Like with fibrinogen, any role of S100A9 in the AD process is unclear, but the focus is again turned towards inflammatory brain processes affecting the AD progression. Interestingly, traumatic brain injury promotes S100A9 amyloid formation, and these plaques may possibly serve as precursor plaques for Aβ …”