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Horvath, I., Iashchishyn, I., Moskalenko, R. A., Wang, C., Warmlander, S. K. T., Wallin, C., . . . Morozova-Roche, L. (2018). Co-aggregation of pro-inflammatory S100A9 with alpha-synuclein in Parkinson's disease: ex vivo and in vitro studies. Journal of Neuroinflammation, 15, Article ID 172.
Open this publication in new window or tab >>Co-aggregation of pro-inflammatory S100A9 with alpha-synuclein in Parkinson's disease: ex vivo and in vitro studies
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2018 (English)In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 15, article id 172Article in journal (Refereed) Published
Abstract [en]

Background: Chronic 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 alpha-synuclein (alpha-syn) and S100A9 both in vitro and ex vivo in PD brain.

Methods: Single and sequential immunohistochemistry, immunofluorescence, scanning electron and atomic force (AFM) microscopies were used to analyze the ex vivo PD brain tissues for S100A9 and alpha-syn location and aggregation. In vitro studies revealing S100A9 and alpha-syn interaction and co-aggregation were conducted by NMR, circular dichroism, Thioflavin-T fluorescence, AFM, and surface plasmon resonance methods.

Results: Co-localized and co-aggregated S100A9 and alpha-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 mu m outer diameter, with S100A9 and alpha-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 alpha-syn were shown to interact with each other via the alpha-syn C-terminus with an apparent dissociation constant of ca. 5 mu M. 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 alpha-syn, while co-aggregation of both proteins mitigated the cytotoxicity of S100A9 oligomers.

Conclusions: We suggest that sustained neuroinflammation promoting the spread of amyloidogenic S100A9 in the brain tissues may trigger the amyloid cascade involving alpha-syn and S100A9 and leading to PD, similar to the effect of S100A9 and A beta 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.

Place, publisher, year, edition, pages
BioMed Central, 2018
Keywords
S100A9, alpha-Synuclein, Parkinson's disease, Neuroinflammation, Amyloid, Cytotoxicity
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-150174 (URN)10.1186/s12974-018-1210-9 (DOI)000434209800001 ()29866153 (PubMedID)
Funder
Västerbotten County Council, ALFVLL-369861Swedish Research Council, 2014-3241The Swedish Brain Foundation
Available from: 2018-07-18 Created: 2018-07-18 Last updated: 2018-07-19Bibliographically approved
Iashchishyn, I. A., Gruden, M. A., Moskalenko, R. A., Davydova, T. V., Wang, C., Sewell, R. D. E. & Morozova-Roche, L. A. (2018). Intranasally Administered S100A9 Amyloids Induced Cellular Stress, Amyloid Seeding, and Behavioral Impairment in Aged Mice. ACS Chemical Neuroscience, 9(6), 1338-1348
Open this publication in new window or tab >>Intranasally Administered S100A9 Amyloids Induced Cellular Stress, Amyloid Seeding, and Behavioral Impairment in Aged Mice
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2018 (English)In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 9, no 6, p. 1338-1348Article in journal (Refereed) Published
Abstract [en]

Amyloid formation and neuroinflammation are major features of Alzheimer's disease pathology. Proinflammatory mediator S100A9 was shown to act as a link between the amyloid and neuroinflammatory cascades in Alzheimer's disease, leading together with Aβ to plaque formation, neuronal loss and memory impairment. In order to examine if S100A9 alone in its native and amyloid states can induce neuronal stress and memory impairment, we have administered S100A9 species intranasally to aged mice. Single and sequential immunohistochemistry and passive avoidance behavioral test were conducted to evaluate the consequences. Administered S100A9 species induced widespread cellular stress responses in cerebral structures, including frontal lobe, hippocampus and cerebellum. These were manifested by increased levels of S100A9, Box, and to a lesser extent activated caspase-3 immunopositive cells. Upon administration of S100A9 fibrils, the amyloid oligomerization was observed in the brain tissues, which can further exacerbate cellular stress. The cellular stress responses correlated with significantly increased training and decreased retention latencies measured in the passive avoidance test for the SI00A9 treated animal groups. Remarkably, the effect size in the behavioral tests was moderate already in the group treated with native S100A9, while the effect sizes were large in the groups administered S100A9 amyloid oligomers or fibrils. The findings demonstrate the brain susceptibility to neurotoxic damage of S100A9 species leading to behavioral and memory impairments. Intranasal administration of S100A9 species proved to be an effective method to study amyloid induced brain dysfunctions, and 5100A9 itself may be postulated as a target to allay early stage neurodegenerative and neuroinflammatory processes.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
Keywords
Aged mice, amyloid, apoptosis, BAX, activated caspase-3, cellular stress, learning and memory, neuroinflammation, S100A9
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-150871 (URN)10.1021/acschemneuro.7b00512 (DOI)000436211800016 ()29618200 (PubMedID)2-s2.0-85048764488 (Scopus ID)
Available from: 2018-09-03 Created: 2018-09-03 Last updated: 2018-09-03Bibliographically approved
Wang, C., Iashchishyn, I., Pansieri, J., Nyström, S., Klementieva, O., Kara, J., . . . Morozova-Roche, L. (2018). S100A9-Driven Amyloid-Neuroinflammatory Cascade in Traumatic Brain Injury as a Precursor State for Alzheimer's Disease. Scientific Reports, 8, Article ID 12836.
Open this publication in new window or tab >>S100A9-Driven Amyloid-Neuroinflammatory Cascade in Traumatic Brain Injury as a Precursor State for Alzheimer's Disease
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 12836Article in journal (Refereed) Published
Abstract [en]

Pro-inflammatory and amyloidogenic S100A9 protein is an important contributor to Alzheimer's disease (AD) pathology. Traumatic brain injury (TBI) is viewed as a precursor state for AD. Here we have shown that S100A9-driven amyloid-neuroinflammatory cascade was initiated in TBI and may serve as a mechanistic link between TBI and AD. By analyzing the TBI and AD human brain tissues, we demonstrated that in post-TBI tissues S100A9, produced by neurons and microglia, becomes drastically abundant compared to A beta and contributes to both precursor-plaque formation and intracellular amyloid oligomerization. Conditions implicated in TBI, such as elevated S100A9 concentration, acidification and fever, provide strong positive feedback for S100A9 nucleation-dependent amyloid formation and delay in its proteinase clearance. Consequently, both intracellular and extracellular S100A9 oligomerization correlated with TBI secondary neuronal loss. Common morphology of TBI and AD plaques indicated their similar initiation around multiple aggregation centers. Importantly, in AD and TBI we found S100A9 plaques without A beta. S100A9 and A beta plaque pathology was significantly advanced in AD cases with TBI history at earlier age, signifying TBI as a risk factor. These new findings highlight the detrimental consequences of prolonged post-TBI neuroinflammation, which can sustain S100A9-driven amyloid-neurodegenerative cascade as a specific mechanism leading to AD development.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:umu:diva-151784 (URN)10.1038/s41598-018-31141-x (DOI)000442870300014 ()30150640 (PubMedID)
Funder
Swedish Institute
Available from: 2018-09-14 Created: 2018-09-14 Last updated: 2018-09-14Bibliographically approved
Wang, C., Iashchishyn, I., Nyström, S., Klementieva, O., Kara, J., Bengtsson, S., . . . Morozova-Roche, L.S100A9-driven amyloid-neuroinflammatory cascade in traumatic brain injury as a risk factor for Alzheimer’s disease.
Open this publication in new window or tab >>S100A9-driven amyloid-neuroinflammatory cascade in traumatic brain injury as a risk factor for Alzheimer’s disease
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(English)Manuscript (preprint) (Other academic)
Keywords
Traumatic brain injury, Alzheimer’s disease, Aβ, S100A9, Amyloid, Cytotoxicity; Neuroinflammation
National Category
Other Medical Sciences not elsewhere specified
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-125077 (URN)
External cooperation:
Projects
Role of pro-inflammatory S100A9 protein in amyloid-neuroinflammatory cascade in Alzheimer’s disease and traumatic brain injury
Available from: 2016-09-05 Created: 2016-09-05 Last updated: 2018-06-07
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-2342-0337

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