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Morozova-Roche, LudmillaORCID iD iconorcid.org/0000-0001-5886-2023
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Publications (10 of 101) Show all publications
Huang, Q., Sun, D., Hussain, M. Z., Liu, Y., Morozova-Roche, L. & Zhang, C. (2019). HEWL interacts with dissipated oleic acid micelles, and decreases oleic acid cytotoxicity. PLoS ONE, 14(2), Article ID e0212648.
Open this publication in new window or tab >>HEWL interacts with dissipated oleic acid micelles, and decreases oleic acid cytotoxicity
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2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 2, article id e0212648Article in journal (Refereed) Published
Abstract [en]

Senile plaques are well-known hallmarks of Alzheimer's Diseases (AD). However, drugs targeting tangles of the protein tau and plaques of beta-amyloid have no significant effect on disease progression, and the studies on the underlying mechanism of AD remain in high demand. Growing evidence supports the protective role of senile plaques in local inflammation driven by S100A9. We herein demonstrate that oleic acid (OA) micelles interact with hen egg white lysozyme (HEWL) and promote its amyloid formation. Consequently, SH-SY5Y cell line and mouse neural stem cells are rescued from OA toxicity by co-aggregation of OA and HEWL. Using atomic force microscopy in combination with fluorescence microscopy, we revealed that HEWL forms round-shaped aggregates in the presence of OA micelles instead of protofibrils of HEWL alone. These HEWL amyloids act as a sink for toxic OA micelles and their co-aggregate form large clumps, suggesting a protective function in amyloid and OA cytotoxicity.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2019
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-157530 (URN)10.1371/journal.pone.0212648 (DOI)000459709100105 ()30794655 (PubMedID)
Available from: 2019-04-01 Created: 2019-04-01 Last updated: 2019-04-01Bibliographically approved
Wang, C., Iashchishyn, I., Kara, J., Fodera, V., Vetri, V., Sancataldo, G., . . . Morozova-Roche, L. (2019). Proinflammatory and amyloidogenic S100A9 induced by traumatic brain injury in mouse model. Neuroscience Letters, 699, 199-205
Open this publication in new window or tab >>Proinflammatory and amyloidogenic S100A9 induced by traumatic brain injury in mouse model
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2019 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 699, p. 199-205Article in journal (Refereed) Published
Abstract [en]

Traumatic brain injury (TBI) represents a significant risk factor for development of neurodegenerative diseases such as Alzheimer's and Parkinson's. The S100A9-driven amyloid-neuroinflammatory cascade occurring during primary and secondary TBI events can serve as a mechanistic link between TBI and Alzheimer's as demonstrated recently in the human brain tissues. Here by using immunohistochemistry in the controlled cortical impact TBI mouse model we have found pro-inflammatory S100A9 in the brain tissues of all mice on the first and third post- TBI days, while 70% of mice did not show any S100A9 presence on seventh post-TBI day similar to controls. This indicates that defensive mechanisms effectively cleared S100A9 in these mouse brain tissues during post-TBI recovery. By using sequential immunohistochemistry we have shown that S100A9 was produced by both neuronal and microglial cells. However, A beta peptide deposits characteristic for Alzheimer's disease were not detected in any post-TBI animals. On the first and third post-TBI days S100A9 was found to aggregate intracellularly into amyloid oligomers, similar to what was previously observed in human TBI tissues. Complementary, by using Rayleigh scatting, intrinsic fluorescence and atomic force microscopy we demonstrated that in vitro S100A9 self- assembles into amyloid oligomers within minutes. Its amyloid aggregation is highly dependent on changes of environmental conditions such as variation of calcium levels, pH, temperature and reduction/oxidation, which might be relevant to perturbation of cellular and tissues homeostasis under TBI. Present results demonstrate that S100A9 induction mechanisms in TBI are similar in mice and humans, emphasizing that S100A9 is an important marker of brain injury and therefore can be a potential therapeutic target.

Place, publisher, year, edition, pages
ELSEVIER IRELAND LTD, 2019
Keywords
Alzheimer's disease, Amyloid, Neuroinflammation, Oligomerization, S100A9, Traumatic brain injury
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-158949 (URN)10.1016/j.neulet.2019.02.012 (DOI)000465055200032 ()30753908 (PubMedID)
Available from: 2019-05-27 Created: 2019-05-27 Last updated: 2019-05-27Bibliographically approved
Pansieri, J., Ostojic, L., Iashchishyn, I., Magzoub, M., Wallin, C., Warmlander, S. K. T., . . . Morozova-Roche, L. (2019). Pro-Inflammatory S100A9 Protein Aggregation Promoted by NCAM1 Peptide Constructs. ACS Chemical Biology, 14(7), 1410-1417
Open this publication in new window or tab >>Pro-Inflammatory S100A9 Protein Aggregation Promoted by NCAM1 Peptide Constructs
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2019 (English)In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 14, no 7, p. 1410-1417Article in journal (Refereed) Published
Abstract [en]

Amyloid cascade and neuroinflammation are hallmarks of neurodegenerative diseases, and pro-inflammatory S100A9 protein is central to both of them. Here, we have shown that NCAM1 peptide constructs carrying polycationic sequences derived from A beta peptide (KKLVFF) and PrP protein (KKRPKP) significantly promote the S100A9 amyloid self-assembly in a concentration-dependent manner by making transient interactions with individual S100A9 molecules, perturbing its native structure and acting as catalysts. Since the individual molecule misfolding is a rate-limiting step in S100A9 amyloid aggregation, the effects of the NCAM1 construct on the native S100A9 are so critical for its amyloid self-assembly. S100A9 rapid self assembly into large aggregated clumps may prevent its amyloid tissue propagation, and by modulating S100A9 aggregation as a part of the amyloid cascade, the whole process may be effectively tuned.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2019
National Category
Biophysics
Identifiers
urn:nbn:se:umu:diva-162010 (URN)10.1021/acschembio.9b00394 (DOI)000476957100005 ()31194501 (PubMedID)
Available from: 2019-08-13 Created: 2019-08-13 Last updated: 2019-08-13Bibliographically approved
Williamson, P. T. F., Horrocks, J., Maheswaran, L., Concistre, M. & Morozova-Roche, L. (2019). Unravelling the Role of S100A9 in the Development of Neurodegenerative Disease. Paper presented at 63rd Annual Meeting of the Biophysical-Society, MAR 02-06, 2019, Baltimore, MD. Biophysical Journal, 116(3), 338A-338A
Open this publication in new window or tab >>Unravelling the Role of S100A9 in the Development of Neurodegenerative Disease
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2019 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 116, no 3, p. 338A-338AArticle in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
CELL PRESS, 2019
National Category
Biophysics
Identifiers
urn:nbn:se:umu:diva-157778 (URN)10.1016/j.bpj.2018.11.1843 (DOI)000460779801690 ()
Conference
63rd Annual Meeting of the Biophysical-Society, MAR 02-06, 2019, Baltimore, MD
Available from: 2019-04-10 Created: 2019-04-10 Last updated: 2019-04-10Bibliographically approved
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
Baldassarre, M., Baronio, C. M., Morozova-Roche, L. A. & Barth, A. (2017). Amyloid beta-peptides 1-40 and 1-42 form oligomers with mixed beta-sheets. Chemical Science, 8(12), 8247-8254
Open this publication in new window or tab >>Amyloid beta-peptides 1-40 and 1-42 form oligomers with mixed beta-sheets
2017 (English)In: Chemical Science, ISSN 2041-6520, E-ISSN 2041-6539, Vol. 8, no 12, p. 8247-8254Article in journal (Refereed) Published
Abstract [en]

Two main amyloid-beta peptides of different length (A beta(40) and A beta(42)) are involved in Alzheimer's disease. Their relative abundance is decisive for the severity of the disease and mixed oligomers may contribute to the toxic species. However, little is know about the extent of mixing. To study whether A beta(40) and A beta(42) co-aggregate, we used Fourier transform infrared spectroscopy in combination with C-13-labeling and spectrum calculation and focused on the amide I vibration, which is sensitive to backbone structure. Mixtures of monomeric labeled A beta(40) and unlabeled A beta(42) (and vice versa) were co-incubated for similar to 20 min and their infrared spectrum recorded. The position of the main C-13-amide I' band shifted to higher wavenumbers with increasing admixture of C-12-peptide due to the presence of C-12-amides in the vicinity of C-13-amides. The results indicate that A beta(40) and A beta(42) form mixed oligomers with a largely random distribution of A beta(40) and A beta(42) strands in their beta-sheets. The structures of the mixed oligomers are intermediate between those of the pure oligomers. There is no indication that one of the peptides forces the backbone structure of its oligomers on the other peptide when they are mixed as monomers. We also demonstrate that isotope-edited infrared spectroscopy can distinguish aggregation modulators that integrate into the backbone structure of their interaction partner from those that do not. As an example for the latter case, the pro-inflammatory calcium binding protein S100A9 is shown not to incorporate into the b-sheets of A beta(42).

Place, publisher, year, edition, pages
ROYAL SOC CHEMISTRY, 2017
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-142960 (URN)10.1039/c7sc01743j (DOI)000415877000043 ()
Available from: 2017-12-14 Created: 2017-12-14 Last updated: 2018-06-09Bibliographically approved
Gruden, M. A., Davydova, T. V., Fomina, V. G., Vetrile, L. A., Morozova-Roche, L. A. & Sewell, R. D. (2017). Antibodies to Glutamate Reversed the Amnesic Effects of Proinflammatory S100A9 Protein Fibrils in Aged C57Bl/6 Mice. Bulletin of experimental biology and medicine, 162(4), 430-432
Open this publication in new window or tab >>Antibodies to Glutamate Reversed the Amnesic Effects of Proinflammatory S100A9 Protein Fibrils in Aged C57Bl/6 Mice
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2017 (English)In: Bulletin of experimental biology and medicine, ISSN 0007-4888, E-ISSN 1573-8221, Vol. 162, no 4, p. 430-432Article in journal (Refereed) Published
Abstract [en]

Chronic intranasal administration of fibrillar structures of proinflammatory S100A9 protein impaired passive avoidance learning in old C57Bl/6 mice. Combined treatment with S100A9 fibrils and antibodies to glutamate was followed by an increase in horizontal locomotor activity of animals in the open-field test and did not disturb spatial memory.

Place, publisher, year, edition, pages
SPRINGER, 2017
Keywords
amnesia, S100A9 fibrils, antibodies to glutamate, spatial memory, locomotor activity
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-133432 (URN)10.1007/s10517-017-3632-2 (DOI)000396319700005 ()28239790 (PubMedID)
Available from: 2017-04-21 Created: 2017-04-21 Last updated: 2018-06-09Bibliographically approved
Goldberg, E. L., Asher, J. L., Molony, R. D., Shaw, A. C., Zeiss, C. J., Wang, C., . . . Dixit, V. D. (2017). beta-Hydroxybutyrate deactivates Neutrophil NLRP3 inflammasome to relieve gout flares. Cell reports, 18(9), 2077-2087
Open this publication in new window or tab >>beta-Hydroxybutyrate deactivates Neutrophil NLRP3 inflammasome to relieve gout flares
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2017 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 18, no 9, p. 2077-2087Article in journal (Refereed) Published
Abstract [en]

Aging and lipotoxicity are two major risk factors for gout that are linked by the activation of the NLRP3 inflammasome. Neutrophil-mediated production of interleukin-1 beta (IL-1 beta) drives gouty flares that cause joint destruction, intense pain, and fever. However, metabolites that impact neutrophil inflammasome remain unknown. Here, we identified that ketogenic diet (KD) increases beta-hydroxybutyrate (BHB) and alleviates urate crystal-induced gout without impairing immune defense against bacterial infection. BHB inhibited NLRP3 inflammasome in S100A9 fibril-primed and urate crystal-activated macrophages, which serve to recruit inflammatory neutrophils in joints. Consistent with reduced gouty flares in rats fed a ketogenic diet, BHB blocked IL-1 beta in neutrophils in a NLRP3-dependent manner in mice and humans irrespective of age. Mechanistically, BHB inhibited the NLRP3 inflammasome in neutrophils by reducing priming and assembly steps. Collectively, our studies show that BHB, a known alternate metabolic fuel, is also an anti-inflammatory molecule that may serve as a treatment for gout.

National Category
Cell and Molecular Biology Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-133663 (URN)10.1016/j.celrep.2017.02.004 (DOI)000397328400002 ()28249154 (PubMedID)
Available from: 2017-04-25 Created: 2017-04-25 Last updated: 2018-06-09Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0001-5886-2023

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