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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.

SUBMITTER: Wang C

PROVIDER: S-EPMC4148179 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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

Wang Chao C Klechikov Alexey G AG Gharibyan Anna L AL Wärmländer Sebastian K T S SK Jarvet Jüri J Zhao Lina L Jia Xueen X Narayana Vinod K VK Shankar S K SK Olofsson Anders A Brännström Thomas T Mu Yuguang Y Gräslund Astrid A Morozova-Roche Ludmilla A LA

Acta neuropathologica 20131116 4

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 a ...[more]

PMID: 24240735

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Project description:BackgroundChronic neuroinflammation is a hallmark of Parkinson's disease (PD) pathophysiology, associated with increased levels of pro-inflammatory factors in PD brain tissues. The pro-inflammatory mediator and highly amyloidogenic protein S100A9 is involved in the amyloid-neuroinflammatory cascade in Alzheimer's disease. This is the first report on the co-aggregation of α-synuclein (α-syn) and S100A9 both in vitro and ex vivo in PD brain.MethodsSingle and sequential immunohistochemistry, immunofluorescence, scanning electron and atomic force (AFM) microscopies were used to analyze the ex vivo PD brain tissues for S100A9 and α-syn location and aggregation. In vitro studies revealing S100A9 and α-syn interaction and co-aggregation were conducted by NMR, circular dichroism, Thioflavin-T fluorescence, AFM, and surface plasmon resonance methods.ResultsCo-localized and co-aggregated S100A9 and α-syn were found in 20% Lewy bodies and 77% neuronal cells in the substantia nigra; both proteins were also observed in Lewy bodies in PD frontal lobe (Braak stages 4-6). Lewy bodies were characterized by ca. 10-23 μm outer diameter, with S100A9 and α-syn being co-localized in the same lamellar structures. S100A9 was also detected in neurons and blood vessels of the aged patients without PD, but in much lesser extent. In vitro S100A9 and α-syn were shown to interact with each other via the α-syn C-terminus with an apparent dissociation constant of ca. 5 μM. Their co-aggregation occurred significantly faster and led to formation of larger amyloid aggregates than the self-assembly of individual proteins. S100A9 amyloid oligomers were more toxic than those of α-syn, while co-aggregation of both proteins mitigated the cytotoxicity of S100A9 oligomers.ConclusionsWe suggest that sustained neuroinflammation promoting the spread of amyloidogenic S100A9 in the brain tissues may trigger the amyloid cascade involving α-syn and S100A9 and leading to PD, similar to the effect of S100A9 and Aβ co-aggregation in Alzheimer's disease. The finding of S100A9 involvement in PD may open a new avenue for therapeutic interventions targeting S100A9 and preventing its amyloid self-assembly in affected brain tissues.

Dataset Information

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

Publications

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

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