Pro-inflammatory S100A9 Protein as a Robust Biomarker Differentiating Early Stages of Cognitive Impairment in Alzheimer’s Disease

Horváth, István; Jia, Xueen; Johansson, Per; Wang, Chao; Moskalenko, Roman; Steinau, Andreas; Forsgren, Lars; Wågberg, Thomas; Svensson, Johan; Zetterberg, Henrik; Morozova‐Roche, Ludmilla A.

doi:10.1021/acschemneuro.5b00265

Cited by 57 publications

(48 citation statements)

References 24 publications

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“…In a previous study, CSF concentrations of Aβ 1–42 as well as the pro-inflammatory protein S100A9 (MRP14) were decreased in AD patients and in the post-mortem brain, immunohistochemical analyses showed intense co-localized immunostaining of S100A9 and Aβ [51]. This possibly suggests that S100A9, like Aβ 1–42 , could be low in CSF of AD patients due to increased aggregation/sequestration of S100A9 in the AD brain.…”

Section: Discussionmentioning

confidence: 92%

Reduced cerebrospinal fluid concentration of interleukin-12/23 subunit p40 in patients with cognitive impairment

et al. 2017

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BackgroundThe role of inflammation in Alzheimer’s disease (AD) and other cognitive disorders is unclear. In a well-defined mono-center population, we measured cytokines and chemokines in paired serum and cerebrospinal fluid (CSF) samples.MethodsConsecutive patients with AD (n = 30), stable mild cognitive impairment (SMCI, n = 11), other dementias (n = 11), and healthy controls (n = 18) were included. None of the subjects was treated with glucocorticoids, cholinesterase inhibitors, or non-steroidal anti-inflammatory drugs. Serum and CSF concentrations of interleukin-6 (IL-6), IL-8, IL-12/23 p40, IL-15, IL-16, vascular endothelial growth factor-A (VEGF-A), and three chemokines were measured using a multiplex panel.ResultsAfter correction for multiple comparisons, only CSF IL-12/23 p40 concentration differed significantly between the total patient group (n = 52) and controls (n = 18; p = 0.002). Further analyses showed that CSF IL-12/23 p40 concentration was decreased in all patient subgroups (AD, other dementias, and SMCI) compared to healthy controls (p < 0.01, p < 0.05, and p < 0.05, respectively). In the total study population (n = 70), CSF IL-12/23 p40 concentrations correlated positively with CSF concentrations of β-amyloid1-42 (Aβ1–42) and phosphorylated tau protein (P-tau) whereas in AD patients (n = 30), CSF IL-12/23 p40 only correlated positively with CSF P-Tau (r = 0.46, p = 0.01).ConclusionsMost cytokines and chemokines were similar in patients and controls, but CSF IL-12/23 subunit p40 concentration was decreased in patients with cognitive impairment, and correlated with markers of AD disease status. Further studies are needed to evaluate the role of CSF IL-12/23 p40 in other dementias and SMCI.

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Section: Discussionmentioning

confidence: 92%

Reduced cerebrospinal fluid concentration of interleukin-12/23 subunit p40 in patients with cognitive impairment

et al. 2017

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“…45 Both A9 and A8/A9 are primary biomarkers for many human inflammatory diseases. [46][47][48][49][50] Further, dysregulation of A9 is associated with various cancers, pulmonary disorders, and Alzheimer's disease. 19,[46][47][48][49][50][51][52] Understanding the mechanisms by which A9 performs its innate immune functions is critical for developing treatments for A9mediated diseases.…”

Section: Introductionmentioning

confidence: 99%

Evolution of multifunctionality through a pleiotropic substitution in the innate immune protein S100A9

Harman

Loes

Warren

et al. 2020

eLife

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Multifunctional proteins are evolutionary puzzles: how do proteins evolve to satisfy multiple functional constraints? S100A9 is one such multifunctional protein. It potently amplifies inflammation via Toll-like receptor four and is antimicrobial as part of a heterocomplex with S100A8. These two functions are seemingly regulated by proteolysis: S100A9 is readily degraded, while S100A8/S100A9 is resistant. We take an evolutionary biochemical approach to show that S100A9 evolved both functions and lost proteolytic resistance from a weakly proinflammatory, proteolytically resistant amniote ancestor. We identify a historical substitution that has pleiotropic effects on S100A9 proinflammatory activity and proteolytic resistance but has little effect on S100A8/S100A9 antimicrobial activity. We thus propose that mammals evolved S100A8/S100A9 antimicrobial and S100A9 proinflammatory activities concomitantly with a proteolytic ‘timer’ to selectively regulate S100A9. This highlights how the same mutation can have pleiotropic effects on one functional state of a protein but not another, thus facilitating the evolution of multifunctionality.

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“…Upcoming evidence shows that CLP might also be involved in cancer development, obesity, progression of dementia, and formation of the atherosclerotic plaque. [5][6][7][8][9][10] CLP, being stable at room temperature, is a candidate biomarker in inflammatory diseases and its levels in stools are routinely measured in the followup of inflammatory bowel diseases. 9 Serum levels are usually reported below 1 mg/ml in healthy subjects, but during inflammation they may increase by 100 times.…”

Section: Introductionmentioning

confidence: 99%

Calprotectin in rheumatic diseases

Ometto

Friso

Astorri

et al. 2016

Exp Biol Med (Maywood)

136

105

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Calprotectin is an acute-phase protein produced by monocytes and neutrophils in the circulation and inflamed tissues. Calprotectin seems to be more sensitive than CRP, being able to detect minimal residual inflammation and is a candidate biomarker in inflammatory diseases. High serum levels are associated with some severe manifestations of rheumatic diseases, such as glomerulonephritis and lung fibrosis. Calprotectin levels in other fluids, such as saliva and synovial fluid, might be helpful in the diagnosis of rheumatic diseases. Of interest is also the potential role of calprotectin as a target of treatment. AbstractCalprotectin is a heterodimer formed by two proteins, S100A8 and S100A9, which are mainly produced by activated monocytes and neutrophils in the circulation and in inflamed tissues. The implication of calprotectin in the inflammatory process has already been demonstrated, but its role in the pathogenesis, diagnosis, and monitoring of rheumatic diseases has gained great attention in recent years. Calprotectin, being stable at room temperature, is a candidate biomarker for the follow-up of disease activity in many autoimmune disorders, where it can predict response to treatment or disease relapse. There is evidence that a number of immunomodulators, including TNF-a inhibitors, may reduce calprotectin expression. S100A8 and S100A9 have a potential role as a target of treatment in murine models of autoimmune disorders, since the direct or indirect blockade of these proteins results in amelioration of the disease process. In this review, we will go over the biologic functions of calprotectin which might be involved in the etiology of rheumatic disorders. We will also report evidence of its potential use as a disease biomarker.

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Pro-inflammatory S100A9 Protein as a Robust Biomarker Differentiating Early Stages of Cognitive Impairment in Alzheimer’s Disease

Cited by 57 publications

References 24 publications

Reduced cerebrospinal fluid concentration of interleukin-12/23 subunit p40 in patients with cognitive impairment

Reduced cerebrospinal fluid concentration of interleukin-12/23 subunit p40 in patients with cognitive impairment

Evolution of multifunctionality through a pleiotropic substitution in the innate immune protein S100A9

Calprotectin in rheumatic diseases

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