Proteomic signatures of neuroinflammation in Alzheimer’s disease, multiple sclerosis and ischemic stroke

Thygesen, Camilla; Larsen, Martin R.; Finsen, Bente

doi:10.1080/14789450.2019.1633919

Cited by 15 publications

(10 citation statements)

References 93 publications

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“…Several studies have evaluated neuroinflammatory features in AD CSF or plasma, with diverse findings such as decreased levels of IL-8 or increased levels of GFAP [5,6]. A recent review described increases in eleven inflammatory proteins in AD in at least two CSF studies, whereas only one was decreased [7]. Of the studies reviewed, only two included MCI patients, none of which made distinction between MCI due to AD and stable MCI [8,9].…”

Section: Introductionmentioning

confidence: 99%

Different Inflammatory Signatures in Alzheimer’s Disease and Frontotemporal Dementia Cerebrospinal Fluid

Boström

Freyhult

Virhammar

et al. 2021

JAD

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Background: Neuroinflammatory processes are common in neurodegenerative diseases such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD), but current knowledge is limited as to whether cerebrospinal fluid (CSF) levels of neuroinflammatory proteins are altered in these diseases. Objective: To identify and characterize neuroinflammatory signatures in CSF from patients with AD, mild cognitive impairment (MCI), and FTD. Methods: We used proximity extension assay and ANOVA to measure and compare levels of 92 inflammatory proteins in CSF from 42 patients with AD, 29 with MCI due to AD (MCI/AD), 22 with stable MCI, 42 with FTD, and 49 control subjects, correcting for age, gender, collection unit, and multiple testing. Results: Levels of matrix metalloproteinase-10 (MMP-10) were increased in AD, MCI/AD, and FTD compared with controls (AD: fold change [FC] = 1.32, 95%confidence interval [CI] 1.14–1.53, q = 0.018; MCI/AD: FC = 1.53, 95%CI 1.20–1.94, q = 0.045; and FTD: FC = 1.42, 95%CI 1.10–1.83, q = 0.020). MMP-10 and eleven additional proteins were increased in MCI/AD, compared with MCI (q < 0.05). In FTD, 36 proteins were decreased, while none was decreased in AD or MCI/AD, compared with controls (q < 0.05). Conclusion: In this cross-sectional multi-center study, we found distinct patterns of CSF inflammatory marker levels in FTD and in both early and established AD, suggesting differing neuroinflammatory processes in the two disorders.

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Section: Introductionmentioning

confidence: 99%

Different Inflammatory Signatures in Alzheimer’s Disease and Frontotemporal Dementia Cerebrospinal Fluid

Boström

Freyhult

Virhammar

et al. 2021

JAD

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“…Recently, proteomic approaches are a critical tool to track the changes of proteome and posttranslational modifications in the field of neuroscience (Li et al, 2017;Schanzenbacher et al, 2018;Thygesen et al, 2018;Thygesen et al, 2019). In this study, we analyzed the proteomic and phosphoproteomic remodeling that occurs in the hippocampus of mice following different types of experience to investigate molecular mechanisms underlying experience-dependent remodeling of synapses.…”

Section: Discussionmentioning

confidence: 99%

Experience-induced remodeling of the hippocampal post-synaptic proteome and phosphoproteome

Heo

Kang

Bygrave

et al. 2021

Preprint

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SummaryThe post synaptic density (PSD) of excitatory synapses contains a highly organized protein network with thousands of proteins and is key node in the regulation of synaptic plasticity. To gain new mechanistic insight into experience-induced changes in the PSD, we examined the global dynamics of the PSD proteome and phosphoproteome in mice following various treatments. Mice were trained using an inhibitory avoidance (IA) task and hippocampal PSD fractions were isolated for quantitative proteomic and phosphoproteomics analysis. We used a sequential enrichment strategy to explore the concurrent events of protein expression and phosphorylation in the hippocampal PSD following IA training (IA) or immediate shock (Shock). We identified more than 6,200 proteins and 3,000 phosphoproteins in the sequential strategy covering a total of 7,429 proteins. On the phosphoproteins we identified a total of 9,589 phosphosites. Strikingly, of the significantly IA-regulated proteins and phosphoproteins, a large fraction of the proteins displayed an overall decrease in phosphorylation level. Bioinformatic analysis of proteins and phosphoproteins that were regulated by IA were annotated for an involvement in regulation of glutamate receptor functionality, calcium signaling, and synaptic plasticity. We also identified synaptic kinases, phosphatases and their respective phosphosites regulated by IA training or immediate shock. Furthermore, we found that AMPA receptor surface expression was regulated by protein phosphatase, Mg2+/Mn2+ dependent 1H (Ppm1h). Together, these results unravel the dynamic remodeling of the PSD upon IA learning or immediate shock and serve as a resource for elucidating the synaptic proteome dynamics induced by experience-dependent plasticity.HighlightsThe proteome and phosphoproteome of mouse hippocampal PSD fractions were examined using quantitative phosphoproteomics and bioinformatics following inhibitory avoidance training or non-associative immediate shock.Approximately 6,200 proteins and 3,000 phosphoproteins were identified and quantified in the hippocampal PSD fractions.IA mediates widespread decreases in the abundance and phosphorylation of proteins in the hippocampal PSD fraction.Kinases, phosphatases and their phosphorylation status were dynamically and significantly regulated by IA and immediate shock.Functional validation shows that the protein phosphatase Ppm1h is linked to the regulation of synaptic plasticity in vitro and in vivo.In BriefQuantitative proteomics and phosphoproteomics combined with subcellular protein fractionation and bioinformatic analysis identifies a highly dynamic regulation of synaptic protein phosphorylation at the postsynaptic density following IA training and immediate shock.

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“…Inflammatory mediators exacerbate the production of A␤, the propagation of tau pathology and neuronal loss [7]. Several recent studies have identified increased CSF levels of a wide range of inflammatory markers including in patients with AD in well controlled research cohorts [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Biomarkers of Inflammation Increase with Tau and Neurodegeneration but not with Amyloid-β in a Heterogenous Clinical Cohort

Michopoulou

Prosser

Kipps

et al. 2022

JAD

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Background: Neuroinflammation is an integral part of Alzheimer’s disease (AD) pathology. Inflammatory mediators can exacerbate the production of amyloid-β (Aβ), the propagation of tau pathology and neuronal loss. Objective: To evaluate the relationship between inflammation markers and established markers of AD in a mixed memory clinic cohort. Methods: 105 cerebrospinal fluid (CSF) samples from a clinical cohort under investigation for cognitive complaints were analyzed. Levels of Aβ 42, total tau, and phosphorylated tau were measured as part of the clinical pathway. Analysis of inflammation markers in CSF samples was performed using multiplex immune assays. Participants were grouped according to their Aβ, tau, and neurodegeneration status and the Paris-Lille-Montpellier (PLM) scale was used to assess the likelihood of AD. Results: From 102 inflammatory markers analyzed, 19 and 23 markers were significantly associated with CSF total tau and phosphorylated tau levels respectively (p < 0.001), while none were associated with Aβ 42. The CSF concentrations of 4 inflammation markers were markedly elevated with increasing PLM class indicating increased likelihood of AD (p < 0.001). Adenosine deaminase, an enzyme involved in sleep homeostasis, was the single best predictor of high likelihood of AD (AUROC 0.788). Functional pathway analysis demonstrated a widespread role for inflammation in neurodegeneration, with certain pathways explaining over 30% of the variability in tau values. Conclusion: CSF inflammation markers increase significantly with tau and neurodegeneration, but not with Aβ in this mixed memory clinic cohort. Thus, such markers could become useful for the clinical diagnosis of neurodegenerative disorders alongside the established Aβ and tau measures.

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Proteomic signatures of neuroinflammation in Alzheimer’s disease, multiple sclerosis and ischemic stroke

Cited by 15 publications

References 93 publications

Different Inflammatory Signatures in Alzheimer’s Disease and Frontotemporal Dementia Cerebrospinal Fluid

Different Inflammatory Signatures in Alzheimer’s Disease and Frontotemporal Dementia Cerebrospinal Fluid

Experience-induced remodeling of the hippocampal post-synaptic proteome and phosphoproteome

Biomarkers of Inflammation Increase with Tau and Neurodegeneration but not with Amyloid-β in a Heterogenous Clinical Cohort

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