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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
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
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
Horvath, I., Jia, X., Johansson, P., Wang, C., Moskalenko, R., Steinau, A., . . . Morozova-Roche, L. A. (2016). Pro-inflammatory S100A9 Protein as a Robust Biomarker Differentiating Early Stages of Cognitive Impairment in Alzheimer's Disease [Letter to the editor]. ACS Chemical Neuroscience, 7(1), 34-39
Open this publication in new window or tab >>Pro-inflammatory S100A9 Protein as a Robust Biomarker Differentiating Early Stages of Cognitive Impairment in Alzheimer's Disease
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2016 (English)In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 7, no 1, p. 34-39Article in journal, Letter (Refereed) Published
Abstract [en]

Pro-inflammatory protein S100A9 was established as a biomarker of dementia progression and compared with others such as Aβ1-42 and tau-proteins. CSF samples from 104 stringently diagnosed individuals divided into five subgroups were analyzed, including nondemented controls, stable mild cognitive impairment (SMCI), mild cognitive impairment due to Alzheimer's disease (MCI-AD), Alzheimer's disease (AD), and vascular dementia (VaD) patients. ELISA, dot-blotting, and electrochemical impedance spectroscopy were used as research methods. The S100A9 and Aβ1-42 levels correlated with each other: their CSF content decreased already at the SMCI stage and declined further under MCI-AD, AD, and VaD conditions. Immunohistochemical analysis also revealed involvement of both Aβ1-42 and S100A9 in the amyloid-neuroinflammatory cascade already during SMCI. Tau proteins were not yet altered in SMCI; however their contents increased during MCI-AD and AD, diagnosing later dementia stages. Thus, four biomarkers together, reflecting different underlying pathological causes, can accurately differentiate dementia progression and also distinguish AD from VaD.

Keywords
Alzheimer’s disease, mild cognitive impairment, cerebrospinal fluid, S100A9, Aβ1−42, biomarkers, amyloid, inflammation
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-111351 (URN)10.1021/acschemneuro.5b00265 (DOI)000368567200006 ()26550994 (PubMedID)
Available from: 2015-11-13 Created: 2015-11-13 Last updated: 2018-06-07Bibliographically approved
Wang, C. (2016). Role of pro-inflammatory S100A9 protein in amyloid-neuroinflammatory cascade in Alzheimer’s disease and traumatic brain injury. (Doctoral dissertation). Umeå: Umeå University
Open this publication in new window or tab >>Role of pro-inflammatory S100A9 protein in amyloid-neuroinflammatory cascade in Alzheimer’s disease and traumatic brain injury
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background Traumatic brain injury (TBI) is a complex disease with a spectrum of symptoms and disabilities. Over the past decade TBI has become the focus of research due to growing epidemiological and clinical evidences that TBI incidences are strong risk factors for Alzheimer’s disease (AD). Major pathological hallmarks of AD are massive accumulations of amyloid-β peptide (Aβ) toxic oligomers and plaques. Neuroinflammation is also considered as a common denominator in AD and aging. The epidemiological and experimental studies have supported that non-steroidal anti-inflammatory drugs markedly reduce the age-related prevalence of AD and can slow amyloid deposition by mechanisms that still remain elusive. S100A9 is a multifunctional cytokine with diverse roles in the cell signaling pathways associated with inflammation and cancers. A widespread expression of S100A9 was also reported in many other ailments involving inflammatory processes, such as AD, malaria, cerebral ischemia and TBI, implying that S100A9 may be a universal biomarker of inflammation. The distinctive feature of S100A9 compared to other pro-inflammatory cytokines is its ability to self-assemble into amyloids, which may lead to the loss of its signaling functions and acquired amyloid cytotoxicity, exceeding that of Aβ.

Methods S100A9 properties was studied under various ex vivo and in vitro conditions. First, human and mouse tissues with TBI and AD were subjected to microscopic, immunohistochemical and immunofluorescent techniques. Then, aged mouse treated with native, oligomeric and fibrillary S100A9 was also studied by using behavioral and neurochemical analysis. Moreover, S100A9 was established as a biomarker of dementia progression and compared with others such as Aβ42 and tau proteins, by studying cerebrospinal fluid (CSF) samples from different stages of dementia. Finally, in vitro experiments on S100A9 amyloidogenesis, co-aggregation with Aβ40 and Aβ42, digestion and cytotoxicity were also performed by using spectroscopic, atomic force microscopy and cell biology methods.

Results S100A9-driven amyloid-neuroinflammatory cascade serves as a link between TBI and AD. We have found that S100A9 contributes to the plaque formation and intraneuronal responses in AD, being a part of the amyloid-neuroinflammatory cascade. In TBI we have found that extensive S100A9 neuronal production and amyloid self-assembly is triggered immediately after injury, leading to apoptotic pathways and neuronal loss. S100A9 is an integral component of both TBI precursor-plaques, formed prior to Aβ deposition, and AD plaques, characterized by different degree of amyloid maturation, indicating that all plaques are associated with inflammation. Both intra- and extracellular amyloid-neuroinflammatory cascades are intertwined and showed similar tendencies in human and mouse tissues in TBI and AD. Ex vivo findings are further supported by in vitro experiments on S100A9 amyloidogenesis, digestion and cytotoxicity. Importantly, being highly amyloidogenic itself, S100A9 can trigger and aggravate Aβ amyloid self-assembly and significantly contribute to amyloid cytotoxicity. Moreover, the CSF dynamics of S100A9 levels matches very closely the content of Aβ42 in AD, vascular dementia and mild cognitive impairment due to AD, emphasizing the involvement of S100A9 together with Aβ in the amyloid-neuroinflammatory cascade in these ailments.

Conclusions The conclusions of this thesis is that the inflammatory pathways and S100A9 specifically represent a potential target for the therapeutic interventions during various post-TBI stages and far prior AD development to halt and reverse these damaging processes.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2016. p. 31
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1838
Keywords
S100A9, Aβ, Alzheimer's disease, Traumatic brain injury, Amyloid, Neuroinflammatory
National Category
Other Medical Sciences not elsewhere specified
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-125078 (URN)978-91-7601-547-6 (ISBN)
External cooperation:
Public defence
2016-09-30, N300, Naturvetarhuset, Umeå, 13:00 (English)
Opponent
Supervisors
Projects
Role of pro-inflammatory S100A9 protein in amyloid-neuroinflammatory cascade in Alzheimer’s disease and traumatic brain injury
Available from: 2016-09-09 Created: 2016-09-05 Last updated: 2018-06-07Bibliographically approved
Gruden, M. A., Davydova, T. V., Wang, C., Narkevich, V. B., Fomina, V. G., Kudrin, V. S., . . . Sewell, R. D. E. (2016). The misfolded pro-inflammatory protein S100A9 disrupts memory via neurochemical remodelling instigating an Alzheimer's disease-like cognitive deficit. Behavioural Brain Research, 306, 106-116
Open this publication in new window or tab >>The misfolded pro-inflammatory protein S100A9 disrupts memory via neurochemical remodelling instigating an Alzheimer's disease-like cognitive deficit
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2016 (English)In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 306, p. 106-116Article in journal (Refereed) Published
Abstract [en]

Memory deficits may develop from a variety of neuropathologies including Alzheimer's disease dementia. During neurodegenerative conditions there are contributory factors such as neuroinflammation and amyloidogenesis involved in memory impairment. In the present study, dual properties of S100A9 protein as a pro-inflammatory and amyloidogenic agent were explored in the passive avoidance memory task along with neurochemical assays in the prefrontal cortex and hippocampus of aged mice. S100A9 oligomers and fibrils were generated in vitro and verified by AFM, Thioflavin T and All antibody binding. Native S100A9 as well as S100A9 oligomers and fibrils or their combination were administered intranasally over 14 days followed by behavioral and neurochemical analysis. Both oligomers and fibrils evoked amnestic activity which correlated with disrupted prefrontal cortical and hippocampal dopaminergic neurochemistry. The oligomer-fibril combination produced similar but weaker neurochemistry to the fibrils administered alone but without passive avoidance amnesia. Native S100A9 did not modify memory task performance even though it generated a general and consistent decrease in monoamine levels (DA, 5-HT and NA) and increased metabolic marker ratios of DA and 5-HT turnover (DOPAC/DA, HVA/DA and 5-HIAA) in the prefrontal cortex. These results provide insight into a novel pathogenetic mechanism underlying amnesia in a fear-aggravated memory task based on amyloidogenesis of a pro-inflammatory factor leading to disrupted brain neurochemistry in the aged brain. The data further suggests that amyloid species of S100A9 create deleterious effects principally on the dopaminergic system and this novel finding might be potentially exploited during dementia management through a neuroprotective strategy.

Keywords
S100A9, Amyloid, Neuroinflammation, Memory, Passive avoidance task, Neurotransmitters, Alzheimer's disease
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-121432 (URN)10.1016/j.bbr.2016.03.016 (DOI)000375513800013 ()26965570 (PubMedID)
Available from: 2016-06-27 Created: 2016-06-02 Last updated: 2018-06-07Bibliographically approved
Gruden, M. A., Davydova, T. V., Narkevich, V. B., Fomina, V. G., Wang, C., Kudrin, V. S., . . . Sewell, R. D. (2015). Noradrenergic and serotonergic neurochemistry arising from intranasal inoculation with α-synuclein aggregates which incite parkinsonian-like symptoms. Behavioural Brain Research, 279, 191-201
Open this publication in new window or tab >>Noradrenergic and serotonergic neurochemistry arising from intranasal inoculation with α-synuclein aggregates which incite parkinsonian-like symptoms
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2015 (English)In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 279, p. 191-201Article in journal (Refereed) Published
Abstract [en]

Alpha-synuclein (α-syn) toxic aggregates delivered by the nasal vector have been shown to modify the neurochemistry of dopamine (DA) which is associated with parkinsonian-like motor symptoms. The aim was therefore to study the intranasal effects of α-syn oligomers, fibrils or their combination on the motor behavior of aged mice in relation to possible noradrenergic and serotonergic correlates. In vitro generated α-syn oligomers and fibrils were verified using atomic force microscopy and the thioflavin T binding assay. Levels of noradrenaline (NA), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were detected using HPLC with electrochemical detection in the substantia nigra (SN) and striatum. The oligomers or fibrils administered alone or in a 50:50 combination (total dose of 0.48mg/kg) were given intranasally for 14 days and "open-field" behaviour was tested on days 0, 15 and 28 of the protocol, at which time brain structures were sampled. Behavioral deficits at the end of the 14-day dosing regime and on day 28 (i.e. 14 days after treatment completion) induced hypokinesia and immobility whilst the aggregate combination additionally produced rigidity. The α-Syn oligomer/fibril mixture also instigated PD-like motor symptoms which correlated heterochronically with elevated NA levels in the striatum but then later in the SN while intranasal fibrils alone augmented 5-HT and 5-HIAA nigral concentrations throughout the protocol. In contrast, α-syn oligomers displayed a delayed serotonin upsurge in the SN. Neurodegenerative and/or actions on neurotransmitter transporters (such as NET, SERT and VMAT2) are discussed as being implicated in these α-syn amyloid induced neurochemical and motoric disturbances.

Keywords
Rodent model, alpha-synuclein oligomers & fibrils, Behavior, Noradrenaline, 5-HT, Metabolism
National Category
Other Basic Medicine
Identifiers
urn:nbn:se:umu:diva-97014 (URN)10.1016/j.bbr.2014.11.001 (DOI)000348255200024 ()25446742 (PubMedID)
Available from: 2014-12-08 Created: 2014-12-08 Last updated: 2018-06-07Bibliographically approved
Gruden, M. A., Davydova, T. V., Narkevich, V. B., Fomina, V. G., Wang, C., Kudrin, V. S., . . . Sewell, R. D. (2014). Intranasal administration of alpha-synuclein aggregates: a Parkinson's disease model with behavioral and neurochemical correlates. Behavioural Brain Research, 263, 158-168
Open this publication in new window or tab >>Intranasal administration of alpha-synuclein aggregates: a Parkinson's disease model with behavioral and neurochemical correlates
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2014 (English)In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 263, p. 158-168Article in journal (Refereed) Published
Abstract [en]

Parkinson's disease (PD) is a neurodegenerative disorder in which both alpha-synuclein (alpha-syn) and dopamine (DA) have a critical role. Our previous studies instigated a novel PD model based on nasal inoculation with alpha-syn aggregates which expressed parkinsonian-like behavioral and immunological features. The current study in mice substantiated the robustness of the amyloid nasal vector model by examining behavioral consequences with respect to DA-ergic neurochemical corollaries. In vitro generated alpha-syn oligomers and fibrils were characterized using atomic force microscopy and the thioflavin T binding assay. These toxic oligomers or fibrils administered alone (0.48 mg/kg) or their 50:50 combination (total dose of 0.48 mg/kg) were given intranasally for 14 days and "open-field" behavior was tested on days 0, 15 and 28 of the protocol. Behavioral deficits at the end of the 14-day dosing regime and on day 28 (i.e., 14 days after treatment completion) induced rigidity, hypokinesia and immobility. This was accompanied by elevated nigral but not striatal DA, DOPAC and HVA concentrations in response to dual administration of alpha-syn oligomers plus fibrils but not the oligomers by themselves. alpha-Syn fibrils intensified not only the hypokinesia and immobility 14 days post treatment, but also reduced vertical rearing and enhanced DA levels in the substantia nigra. Only nigral DA turnover (DOPAC/DA but not HVA/DA ratio) was augmented in response to fibril treatment but there were no changes in the striatum. Compilation of these novel behavioral and neurochemical findings substantiate the validity of the alpha-syn nasal vector model for investigating parkinsonian-like symptoms.

(C) 2014 Elsevier B.V. All rights reserved.

Place, publisher, year, edition, pages
Elsevier, 2014
Keywords
Rodent model; α-synuclein oligomers; Fibrils; Behavior; Dopamine neurochemistry
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:umu:diva-88668 (URN)10.1016/j.bbr.2014.01.017 (DOI)000333883700020 ()
Available from: 2014-05-19 Created: 2014-05-12 Last updated: 2018-06-07Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-7505-8045

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