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The role of pro-inflammatory S100A9 in Alzheimer's disease amyloid-neuroinflammatory cascade
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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2014 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 127, no 4, 507-522 p.Article in journal (Refereed) Published
Abstract [en]

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 A beta. In traumatic brain injury (TBI) S100A9 itself rapidly forms amyloid plaques, which were reactive with oligomer-specific antibodies, but not with A beta 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 A beta protofilaments. S100A9 amyloid cytotoxicity and native S100A9 pro-inflammatory signaling can be mitigated by its co-aggregation with A beta, which results in a variety of micron-scale amyloid complexes. NMR and molecular docking demonstrated transient interactions between native S100A9 and A beta. Thus, abundantly present in AD brain pro-inflammatory S100A9, possessing also intrinsic amyloidogenic properties and ability to modulate A beta aggregation, can serve as a link between the AD amyloid and neuroinflammatory cascades and as a prospective therapeutic target.

Place, publisher, year, edition, pages
2014. Vol. 127, no 4, 507-522 p.
Keyword [en]
A beta, Alzheimer's disease, Amyloid, Cytotoxicity, Neuroinflammation, S100A9, Traumatic brain injury
National Category
Biological Sciences Neurosciences
URN: urn:nbn:se:su:diva-102762DOI: 10.1007/s00401-013-1208-4ISI: 000332957400004OAI: diva2:714082


Available from: 2014-04-25 Created: 2014-04-22 Last updated: 2014-04-25Bibliographically approved

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Wärmländer, Sebastian K. T. S.Jarvet, JüriGräslund, Astrid
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