Change search
ReferencesLink to record
Permanent link

Direct link
The misfolded pro-inflammatory protein S100A9 disrupts memory via neurochemical remodelling instigating an Alzheimer's disease-like cognitive deficit
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Show others and affiliations
2016 (English)In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 306, 106-116 p.Article in journal (Refereed) PublishedText
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.

Place, publisher, year, edition, pages
2016. Vol. 306, 106-116 p.
Keyword [en]
S100A9, Amyloid, Neuroinflammation, Memory, Passive avoidance task, Neurotransmitters, Alzheimer's disease
National Category
URN: urn:nbn:se:umu:diva-121432DOI: 10.1016/j.bbr.2016.03.016ISI: 000375513800013PubMedID: 26965570OAI: diva2:943304
Available from: 2016-06-27 Created: 2016-06-02 Last updated: 2016-09-05Bibliographically approved
In thesis
1. Role of pro-inflammatory S100A9 protein in amyloid-neuroinflammatory cascade in Alzheimer’s disease and traumatic brain injury
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. 31 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1838
S100A9, Aβ, Alzheimer's disease, Traumatic brain injury, Amyloid, Neuroinflammatory
National Category
Other Medical Sciences not elsewhere specified
Research subject
Medical Biochemistry
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)
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: 2016-09-07Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Wang, ChaoMorozova-Roche, Ludmilla A.
By organisation
Department of Medical Biochemistry and Biophysics
In the same journal
Behavioural Brain Research

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 45 hits
ReferencesLink to record
Permanent link

Direct link