1. The role of pro-inflammatory S100A9 in Alzheimer’s disease amyloid-neuroinflammatory cascade
- Author
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Astrid Gräslund, Li Na Zhao, Sebastian K.T.S. Wärmländer, Thomas Brännström, Anders Olofsson, Jüri Jarvet, Alexey Klechikov, Xueen Jia, Ludmilla A. Morozova-Roche, Anna L. Gharibyan, S. K. Shankar, Yuguang Mu, Chao Wang, and School of Biological Sciences
- Subjects
Adult ,Male ,Models, Molecular ,Amyloid ,Cell Survival ,Cytotoxicity ,Clinical Neurology ,Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) ,Plaque, Amyloid ,Hippocampal formation ,Biology ,A beta ,S100A9 ,Pathology and Forensic Medicine ,Cellular and Molecular Neuroscience ,Neuroblastoma ,Traumatic brain injury ,Neuroinflammation ,Alzheimer Disease ,Cell Line, Tumor ,medicine ,Calgranulin B ,Humans ,Senile plaques ,Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) ,Aβ ,Aged ,Cerebral Cortex ,Original Paper ,Amyloid beta-Peptides ,Neurodegeneration ,P3 peptide ,Brain ,Alzheimer's disease ,Middle Aged ,medicine.disease ,Peptide Fragments ,Science::Biological sciences [DRNTU] ,Brain Injuries ,Immunology ,Female ,Neurology (clinical) ,Neuroscience ,Alzheimer’s disease - 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 material The online version of this article (doi:10.1007/s00401-013-1208-4) contains supplementary material, which is available to authorized users.
- Published
- 2013