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Sökning: WFRF:(Hölttä Mikko)

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1.
  • Holtta, Mikko, et al. (författare)
  • An Integrated Workflow for Multiplex CSF Proteomics and Peptidomics-Identification of Candidate Cerebrospinal Fluid Biomarkers of Alzheimer's Disease
  • 2015
  • Ingår i: Journal of Proteome Research. - The American Chemical Society (ACS). - 1535-3893. ; 14:2, s. 654-663
  • Tidskriftsartikel (refereegranskat)abstract
    • Many disease processes in the brain are reflected in the protein composition of the cerebrospinal fluid (CSF). In addition to proteins, CSF also contains a large number of endogenous peptides whose potential as disease biomarkers largely remains to be explored. We have developed a novel workflow in which multiplex isobaric labeling is used for simultaneous quantification of endogenous CSF peptides and proteins by liquid chromatography coupled with mass spectrometry. After the labeling of CSF samples, endogenous peptides are separated from proteins by ultrafiltration. The proteins retained on the filters are trypsinized, and the tryptic peptides are collected separately. We evaluated this technique in a comparative pilot study of CSF peptide and protein profiles in eight patients with Alzheimer's disease (AD) and eight nondemented controls. We identified several differences between the AD and control group among endogenous peptides derived from proteins known to be associated with AD, including neurosecretory protein VGF (ratios AD/controls 0.45-0.81), integral membrane protein 2B (ratios AD/controls 0.72-0.84), and metallothionein-3 (ratios AD/controls 0.51-0.61). Analysis of tryptic peptides identified several proteins that were altered in the AD group, some of which have previously been reported as changed in AD, for example, VGF (ratio AD/controls 0.70).
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2.
  • Holtta, Mikko, et al. (författare)
  • Evaluating Amyloid-beta Oligomers in Cerebrospinal Fluid as a Biomarker for Alzheimer's Disease
  • 2013
  • Ingår i: PLoS ONE. - Public Library of Science. - 1932-6203. ; 8:6
  • Tidskriftsartikel (refereegranskat)abstract
    • The current study evaluated amyloid-beta oligomers (A beta o) in cerebrospinal fluid as a clinical biomarker for Alzheimer's disease (AD). We developed a highly sensitive A beta o ELISA using the same N-terminal monoclonal antibody (82E1) for capture and detection. CSF samples from patients with AD, mild cognitive impairment (MCI), and healthy controls were examined. The assay was specific for oligomerized A beta with a lower limit of quantification of 200 fg/ml, and the assay signal showed a tight correlation with synthetic A beta o levels. Three clinical materials of well characterized AD patients (n = 199) and cognitively healthy controls (n = 148) from different clinical centers were included, together with a clinical material of patients with MCI (n = 165). A beta o levels were elevated in the all three AD-control comparisons although with a large overlap and a separation from controls that was far from complete. Patients with MCI who later converted to AD had increased A beta o levels on a group level but several samples had undetectable levels. These results indicate that presence of high or measurable A beta o levels in CSF is clearly associated with AD, but the overlap is too large for the test to have any diagnostic potential on its own.
3.
  • Akkilic, Namik, et al. (författare)
  • Avidity-Based Affinity Enhancement Using Nanoliposome-Amplified SPR Sensing Enables Low Picomolar Detection of Biologically Active Neuregulin 1
  • 2019
  • Ingår i: ACS Sensors. - 23793694. ; 4:12, s. 3166-3174
  • Tidskriftsartikel (refereegranskat)abstract
    • Biomarkers serve as indicators of disease progression or therapeutic response of an medical intervention, and means for enabling a reliable and sensitive biomarker detection are therefore vital in clinical settings. Most biosensor assays require high-affinity interactions in combination with an enzyme or fluorescent tag to enable detection and frequently employ extensive washing procedures prior to signal readout. Attempts to overcome this limitation by using natural biological partners tend to be demanding, because their very low affinity is frequently not compatible with the need of reaching low limits of detection (LODs), especially for circulating biomarkers that possess short half-lives. To address these challenges, we developed a label-free surface plasmon resonance (SPR) platform for the detection of neuregulin 1 (NRG1) using ErbB4-modified liposomes offering both signal amplification and affinity enhancement via functional multivalent interactions. Through the functional avidity interaction between NRG1 and ErbB4, an LOD of 3.5 picomolar was reached, which is about 60-fold higher than traditional SPR and miniaturized immunoassays. The biosensor displays also an 8-fold higher sensitivity when compared with a single-molecule immunoassay employing the natural binding partner rather than a high-affinity antibody as one of the interaction partners. In fact, the liposome-induced avidity between NRG1 and ErbB4 offered an LOD that was comparable to that obtained using a high-affinity antibody and enabled detection of NRG1 in plasma with a LOD of 36 pM. Employing the liposome-enhanced platform in conjunction with a low-affinity biomarker receptor thus enables the assessment of the functional state of the biomarker at competitive LODs and eliminates the need for high-affinity antibodies.
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4.
  • Hölttä, Mikko, et al. (författare)
  • A single dose of the gamma-secretase inhibitor semagacestat alters the cerebrospinal fluid peptidome in humans
  • 2016
  • Ingår i: Alzheimers Research & Therapy. - 1758-9193. ; 8:11
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: In Alzheimer's disease, beta-amyloid peptides in the brain aggregate into toxic oligomers and plaques, a process which is associated with neuronal degeneration, memory loss, and cognitive decline. One therapeutic strategy is to decrease the production of potentially toxic beta-amyloid species by the use of inhibitors or modulators of the enzymes that produce beta-amyloid from amyloid precursor protein (APP). The failures of several such drug candidates by lack of effect or undesired side-effects underscore the importance to monitor the drug effects in the brain on a molecular level. Here we evaluate if peptidomic analysis in cerebrospinal fluid (CSF) can be used for this purpose. Methods: Fifteen human healthy volunteers, divided into three groups, received a single dose of placebo or either 140 mg or 280 mg of the gamma-secretase inhibitor semagacestat (LY450139). Endogenous peptides in CSF, sampled prior to administration of the drug and at six subsequent time points, were analyzed by liquid chromatography coupled to mass spectrometry, using isobaric labeling based on the tandem mass tag approach for relative quantification. Results: Out of 302 reproducibly detected peptides, 11 were affected by the treatment. Among these, one was derived from APP and one from amyloid precursor-like protein 1. Nine peptides were derived from proteins that may not be gamma-secretase substrates per se, but that are regulated in a gamma-secretase-dependent manner. Conclusions: These results indicate that a CSF peptidomic approach may be a valuable tool both to verify target engagement and to identify other pharmacodynamic effects of the drug. Data are available via ProteomeXchange with identifier PXD003075.
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5.
  • Hölttä, Mikko, et al. (författare)
  • Evaluating amyloid-β oligomers in cerebrospinal fluid as a biomarker for Alzheimer's disease.
  • 2013
  • Ingår i: PLoS ONE. - 1932-6203. ; 8:6
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>The current study evaluated amyloid-β oligomers (Aβo) in cerebrospinal fluid as a clinical biomarker for Alzheimer's disease (AD). We developed a highly sensitive Aβo ELISA using the same N-terminal monoclonal antibody (82E1) for capture and detection. CSF samples from patients with AD, mild cognitive impairment (MCI), and healthy controls were examined. The assay was specific for oligomerized Aβ with a lower limit of quantification of 200 fg/ml, and the assay signal showed a tight correlation with synthetic Aβo levels. Three clinical materials of well characterized AD patients (n = 199) and cognitively healthy controls (n = 148) from different clinical centers were included, together with a clinical material of patients with MCI (n = 165). Aβo levels were elevated in the all three AD-control comparisons although with a large overlap and a separation from controls that was far from complete. Patients with MCI who later converted to AD had increased Aβo levels on a group level but several samples had undetectable levels. These results indicate that presence of high or measurable Aβo levels in CSF is clearly associated with AD, but the overlap is too large for the test to have any diagnostic potential on its own.</p>
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6.
  • Hölttä, Mikko, et al. (författare)
  • Peptidome Analysis of Cerebrospinal Fluid by LC-MALDI MS
  • 2012
  • Ingår i: Plos One. - 1932-6203. ; 7:8
  • Tidskriftsartikel (refereegranskat)abstract
    • We report on the analysis of endogenous peptides in cerebrospinal fluid (CSF) by mass spectrometry. A method was developed for preparation of peptide extracts from CSF. Analysis of the extracts by offline LC-MALDI MS resulted in the detection of 3,000-4,000 peptide-like features. Out of these, 730 peptides were identified by MS/MS. The majority of these peptides have not been previously reported in CSF. The identified peptides were found to originate from 104 proteins, of which several have been reported to be involved in different disorders of the central nervous system. These results support the notion that CSF peptidomics may be viable complement to proteomics in the search of biomarkers of CNS disorders.
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7.
  • Jeppsson, Anna, et al. (författare)
  • Amyloid mis-metabolism in idiopathic normal pressure hydrocephalus
  • 2016
  • Ingår i: Fluids and Barriers of the Cns. - 2045-8118. ; 13
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Patients with idiopathic normal pressure hydrocephalus (iNPH) have reduced cerebrospinal fluid (CSF) concentrations of amyloid-beta (A beta) and alpha- and beta-cleaved soluble forms of amyloid precursor protein (sAPP alpha and sAPP beta). The aims of this study were to examine if changes could also be seen in the CSF for secreted metabolites of APP-like protein 1 (APLP1) and to explore the prognostic value of amyloid-related CSF biomarkers, as well as markers of neuronal injury and astroglial activation, as regards to clinical outcome after shunt surgery. Methods: Twenty patients diagnosed with iNPH, 10 improved and 10 unchanged by shunt surgery, and 20 neurologically healthy controls were included. All patients were examined clinically prior to surgery and at 6-month follow-up after surgery using the iNPH scale. Lumbar puncture was performed pre-operatively. CSF samples were analyzed for neurofilament light (NFL), A beta isoforms A beta 38, A beta 40 and A beta 42, sAPP alpha, sAPP beta, APLP1 beta-derived peptides APL1 beta 25, APL1 beta 27 and APL1 beta 28 and YKL40 by immunochemical methods. Results: The concentrations of all soluble forms of APP, all A beta isoforms and APL1 beta 28 were lower, whilst APL1 beta 25 and APL1 beta 27 were higher in the CSF of iNPH patients compared to controls. There was no difference in biomarker concentrations between patients who improved after surgery and those who remained unchanged. Conclusions: The reduced CSF concentrations of A beta 38, A beta 40, A beta 42, sAPPa and sAPP beta suggest that APP expression could be downregulated in iNPH. In contrast, APLP1 concentration in the CSF seems relatively unchanged. The increase of APL1 beta 25 and APL1 beta 27 in combination with a slight decreased APL1 beta 28 could be caused by more available gamma-secretase due to reduced availability of its primary substrate, APP. The data did not support the use of these markers as indicators of shunt responsiveness.
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8.
  • Magdalinou, N. K., et al. (författare)
  • Identification of candidate cerebrospinal fluid biomarkers in parkinsonism using quantitative proteomics
  • 2017
  • Ingår i: Parkinsonism & Related Disorders. - 1353-8020. ; 37, s. 65-71
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Neurodegenerative parkinsonian syndromes have significant clinical and pathological overlap, making early diagnosis difficult. Cerebrospinal fluid (CSF) biomarkers may aid the differentiation of these disorders, but other than a-synuclein and neurofilament light chain protein, which have limited diagnostic power, specific protein biomarkers remain elusive. Objectives: To study disease mechanisms and identify possible CSF diagnostic biomarkers through discovery proteomics, which discriminate parkinsonian syndromes from healthy controls. Methods: CSF was collected consecutively from 134 participants; Parkinson's disease (n = 26), atypical parkinsonian syndromes (n = 78, including progressive supranuclear palsy (n = 36), multiple system atrophy (n = 28), corticobasal syndrome (n = 14)), and elderly healthy controls (n = 30). Participants were divided into a discovery and a validation set for analysis. The samples were subjected to tryptic digestion, followed by liquid chromatography-mass spectrometry analysis for identification and relative quantification by isobaric labelling. Candidate protein biomarkers were identified based on the relative abundances of the identified tryptic peptides. Their predictive performance was evaluated by analysis of the validation set. Results: 79 tryptic peptides, derived from 26 proteins were found to differ significantly between atypical parkinsonism patients and controls. They included acute phase/inflammatory markers and neuronal/synaptic markers, which were respectively increased or decreased in atypical parkinsonism, while their levels in PD subjects were intermediate between controls and atypical parkinsonism. Conclusion: Using an unbiased proteomic approach, proteins were identified that were able to differentiate atypical parkinsonian syndrome patients from healthy controls. Our study indicates that markers that may reflect neuronal function and/or plasticity, such as the amyloid precursor protein, and inflammatory markers may hold future promise as candidate biomarkers in parkinsonism. (C) 2017 Published by Elsevier Ltd.
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9.
  • Marco, Maugeri , 1983-, et al. (författare)
  • Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells
  • 2019
  • Ingår i: Nature Communications. - 2041-1723. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • RNA-based therapeutics hold great promise for treating diseases and lipid nanoparticles (LNPs) represent the most advanced platform for RNA delivery. However, the fate of the LNP-mRNA after endosome-engulfing and escape from the autophagy-lysosomal pathway remains unclear. To investigate this, mRNA (encoding human erythropoietin) was delivered to cells using LNPs, which shows, for the first time, a link between LNP-mRNA endocytosis and its packaging into extracellular vesicles (endo-EVs: secreted after the endocytosis of LNP-mRNA). Endosomal escape of LNP-mRNA is dependent on the molar ratios between ionizable lipids and mRNA nucleotides. Our results show that fractions of ionizable lipids and mRNA (1:1 molar ratio of hEPO mRNA nucleotides:ionizable lipids) of endocytosed LNPs were detected in endo-EVs. Importantly, these EVs can protect the exogenous mRNA during in vivo delivery to produce human protein in mice, detected in plasma and organs. Compared to LNPs, endo-EVs cause lower expression of inflammatory cytokines.
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10.
  • Mustafiz, Tamanna, et al. (författare)
  • Characterization of the brain β-amyloid isoform pattern at different ages of Tg2576 mice.
  • 2011
  • Ingår i: Neuro-degenerative diseases. - 1660-2862. ; 8:5, s. 352-63
  • Tidskriftsartikel (refereegranskat)abstract
    • Although genetic and biochemical studies have suggested a cardinal role for β-amyloid (Aβ) in Alzheimer's disease, the underlying mechanism(s) of how Aβ induces neurodegeneration is still unclear. Our objective was to investigate the consequences of Aβ, especially on tau phosphorylation at specific epitopes important for Alzheimer's disease.
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