The role of pro-inflammatory S100A9 in Alzheimer's disease amyloid-neuroinflammatory cascadeShow others and affiliations
2014 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 127, no 4, p. 507-522Article 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, p. 507-522
Keywords [en]
A beta, Alzheimer's disease, Amyloid, Cytotoxicity, Neuroinflammation, S100A9, Traumatic brain injury
National Category
Biological Sciences Neurosciences
Identifiers
URN: urn:nbn:se:su:diva-102762DOI: 10.1007/s00401-013-1208-4ISI: 000332957400004OAI: oai:DiVA.org:su-102762DiVA, id: diva2:714082
Note
AuthorCount:13;
2014-04-252014-04-222018-01-11Bibliographically approved