Cerebrospinal fluid markers of extracellular matrix remodelling, synaptic plasticity and neuroinflammation before and after cranial radiotherapy

Fernström, Erik; Minta, Karolina; Andréasson, Ulf; Sandelius, Åsa; Wasling, Pontus; Westman‐Brinkmalm, Ann; Höglund, Kina; Blennow, Kaj; Nyman, Jan; Zetterberg, Henrik; Kalm, Marie

doi:10.1111/joim.12763

Cited by 13 publications

(12 citation statements)

References 81 publications

(109 reference statements)

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“…High-resolution parallel reaction monitoring was performed on a Q Exactive quadropole-orbitrap mass spectrometer coupled to an Ultimate 3000 chromatography system (Thermo Fisher Scientific) for the parallel quantification of SNAP-25 (amino acids 32-40 = SNAP-25aa40 and Ac-2-16 = SNAP-25tot) and synaptotagmin-1 (amino acids 215-228) in CSF. Antibodies included mouse monoclonal antibody SP12 recognising SNAP-25 and mouse monoclonal antibody SM181 recognising an epitope containing the N-terminally acetylated first 11 amino acids of SNAP-25 (as previously described by Brinkmalm et al [13]), and monoclonal antibody clone 41.1 recognising the cytoplasmic portion of synaptotagmin-1 from Synaptic Systems (detailed methods previously described by Öhrfelt et al [14] and Fernström et al [18]).…”

Section: Methodsmentioning

confidence: 99%

CSF synaptic protein concentrations are raised in those with atypical Alzheimer’s disease but not frontotemporal dementia

et al. 2019

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BackgroundIncreased CSF levels of a number of synaptic markers have been reported in Alzheimer’s disease (AD), but little is known about their concentrations in frontotemporal dementia (FTD). We investigated this in three synaptic proteins, neurogranin, SNAP-25, and synaptotagmin-1.MethodsCSF samples were analysed from 66 patients with a disorder in the FTD spectrum and 19 healthy controls. Patients were stratified by their tau to Aβ42 ratio: those with a ratio of > 1 considered as having likely AD pathology, i.e. an atypical form of AD (‘AD biomarker’ group [n = 18]), and < 1 as likely FTD pathology (‘FTD biomarker’ group [n = 48]). A subgroup analysis compared those in the FTD group with likely tau (n = 7) and TDP-43 (n = 18) pathology. Concentrations of neurogranin were measured using two different ELISAs (Ng22 and Ng36), and concentrations of two SNAP-25 fragments (SNAP-25tot and SNAP-25aa40) and synaptotagmin-1 were measured via mass spectrometry.ResultsThe AD biomarker group had significantly higher concentrations of all synaptic proteins compared to controls except for synaptotagmin-1 where there was only a trend to increased levels—Ng22, AD mean 232.2 (standard deviation 138.9) pg/ml, controls 137.6 (95.9); Ng36, 225.5 (148.8) pg/ml, 130.0 (80.9); SNAP-25tot, 71.4 (27.9) pM, 53.5 (11.7); SNAP-25aa40, 14.0 (6.3), 7.9 (2.3) pM; and synaptotagmin-1, 287.7 (156.0) pM, 238.3 (71.4). All synaptic measures were significantly higher in the atypical AD group than the FTD biomarker group except for Ng36 where there was only a trend to increased levels—Ng22, 114.0 (117.5); Ng36, 171.1 (75.2); SNAP-25tot, 49.2 (16.7); SNAP-25aa40, 8.2 (3.4); and synaptotagmin-1, 197.1 (78.9). No markers were higher in the FTD biomarker group than controls. No significant differences were seen in the subgroup analysis, but there was a trend to increased levels in those with likely tau pathology.ConclusionsNo CSF synaptic proteins have been shown to be abnormal in those with likely FTD pathologically. Higher CSF synaptic protein concentrations of neurogranin, SNAP-25, and synaptotagmin-1 appear to be related to AD pathology.

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Section: Methodsmentioning

confidence: 99%

CSF synaptic protein concentrations are raised in those with atypical Alzheimer’s disease but not frontotemporal dementia

et al. 2019

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“…Radiotherapy can affect the expression of extracellular matrix components and ECM remodeling ( 113 , 121 ). For instance, CAF activation following radiation leads to the secretion of numerous ECM proteins ( 113 ).…”

Section: Emt-mediated Mechanisms In Radioresistancementioning

confidence: 99%

Targeting Epithelial-to-Mesenchymal Transition in Radioresistance: Crosslinked Mechanisms and Strategies

et al. 2022

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Radiotherapy exerts a crucial role in curing cancer, however, its treatment efficiency is mostly limited due to the presence of radioresistance. Epithelial-to-mesenchymal transition (EMT) is a biological process that endows the cancer cells with invasive and metastatic properties, as well as radioresistance. Many potential mechanisms of EMT-related radioresistance being reported have broaden our cognition, and hint us the importance of an overall understanding of the relationship between EMT and radioresistance. This review focuses on the recent progresses involved in EMT-related mechanisms in regulating radioresistance, irradiation-mediated EMT program, and the intervention strategies to increase tumor radiosensitivity, in order to improve radiotherapy efficiency and clinical outcomes of cancer patients.

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“…Following prophylactic radiotherapy to the brain, lower levels of extracellular matrix (ECM) proteins in the cerebrospinal fluid from adult small cell lung cancer patients have previously been shown 28 . In line with this, all genes related to ECM showed reduced expression in the current study, indicating a degradation of the ECM following CIR (Fig.…”

Section: Resultsmentioning

confidence: 99%

Chronic disturbance in the thalamus following cranial irradiation to the developing mouse brain

Boström

Eriksson

Danial

et al. 2019

Sci Rep

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Better survival rates among pediatric brain tumor patients have resulted in an increased awareness of late side effects that commonly appear following cancer treatment. Radiation-induced changes in hippocampus and white matter are well described, but do not explain the full range of neurological late effects in childhood cancer survivors. The aim of this study was to investigate thalamus following cranial irradiation (CIR) to the developing brain. At postnatal day 14, male mice pups received a single dose of 8 Gy CIR. Cellular effects in thalamus were assessed using immunohistochemistry 4 months after CIR. Interestingly, the density of neurons decreased with 35% ( p = 0.0431) and the density of astrocytes increased with 44% ( p = 0.011). To investigate thalamic astrocytes, S100β + cells were isolated by fluorescence-activated cell sorting and genetically profiled using next-generation sequencing. The phenotypical characterization indicated a disrupted function, such as downregulated microtubules’ function, higher metabolic activity, immature phenotype and degraded ECM. The current study provides novel insight into that thalamus, just like hippocampus and white matter, is severely affected by CIR. This knowledge is of importance to understand the late effects seen in pediatric brain tumor survivors and can be used to give them the best suitable care.

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Cerebrospinal fluid markers of extracellular matrix remodelling, synaptic plasticity and neuroinflammation before and after cranial radiotherapy

Abstract: To our knowledge, this is the first time ECM-related proteins have been shown to be affected by cranial radiotherapy in patients with cancer. These findings may help us to get a better understanding of the mechanisms behind side effects following radiotherapy.

Cited by 13 publications

References 81 publications

CSF synaptic protein concentrations are raised in those with atypical Alzheimer’s disease but not frontotemporal dementia

CSF synaptic protein concentrations are raised in those with atypical Alzheimer’s disease but not frontotemporal dementia

Targeting Epithelial-to-Mesenchymal Transition in Radioresistance: Crosslinked Mechanisms and Strategies

Chronic disturbance in the thalamus following cranial irradiation to the developing mouse brain

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