| 1. |
- Baker, Crystal, et al.
(author)
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Effects of Alzheimer's peptide and alpha 1-antichymotrypsin on astrocyte gene expression
- 2007
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In: Neurobiology of Aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 28:1, s. 51-61
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Journal article (peer-reviewed)abstract
- We employed gene array technology to investigate the effects of alpha 1-antichymotrypsin (ACT), soluble or fibrillar Alzheimer's peptide (A beta(1-42)) alone and the combination of ACT/A beta(1-42) on human astrocytes. Using a 1.2-fold change as significance threshold, 398 astrocyte genes showed altered expression in response to these treatments compared to controls. Of the 276 genes affected by the ACT/soluble A beta(1-42) combination, 195 (70.6%) were suppressed. The ACT/fibrillar A beta(1-42) combination affected expression of 64 genes of which 58 (90.5%) were up-regulated. The most prominent gene expression changes in response to the ACT/soluble A beta(1-42), were the down-regulation of at least 60 genes involved in transcription, signal transduction, apoptosis and neurogenesis. The ACT/fibril A beta(1-42) increased the expression of genes involved in transcription regulation and signal transduction. Surprisingly, gene expression of astrocytes exposed to soluble or fibrillar A beta(1-42) alone was largely unaffected. Thus, the molecular forms generated by the combination of ACT/A beta(1-42) alter expression of astrocyte genes more profoundly in breadth and magnitude than soluble or fibrillar A beta(1-42) alone, suggesting that pathogenic effects of A beta(1-42) may occur as a consequence of its association with other proteins. (c) 2005 Elsevier Inc. All rights reserved.
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| 2. |
- Martínez-Morillo, E., et al.
(author)
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Assessment of peptide chemical modifications on the development of an accurate and precise multiplex selected reaction monitoring assay for Apolipoprotein e isoforms
- 2014
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In: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 13:2, s. 1077-1087
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Journal article (peer-reviewed)abstract
- Apolipoprotein E (ApoE) is a polymorphic protein that plays a major role in lipid metabolism in the central nervous system and periphery. It has three common allelic isoforms, ApoE2, ApoE3, and ApoE4, that differ in only one or two amino acids. ApoE isoforms have been associated with the occurrence and progression of several pathological conditions, such as coronary atherosclerosis and Alzheimer's disease. The aim of this study was to develop a mass spectrometry (MS)-based assay for absolute quantification of ApoE isoforms in cerebrospinal fluid and plasma samples using isotope-labeled peptides. The assay included five tryptic peptides: CLAVYQAGAR (ApoE2), LGADMEDVCGR (ApoE2 and 3), LAVYQAGAR (ApoE3 and 4), LGADMEDVR (ApoE4), and LGPLVEQGR (total ApoE). Both cerebrospinal fluid and plasma samples were assayed to validate the method. The digestion yield and the extension of chemical modifications in selected amino acid residues (methionine oxidation, glutamine deamidation, and cyclization of N-terminus carbamidomethylcysteine) were also studied. The ApoE phenotype was successfully assigned to all samples analyzed in a blinded manner. The method showed good linearity (R2 > 0.99) and reproducibility (within laboratory imprecision <13%). The comparison of the MS-based assay with an ELISA for total ApoE concentration showed a moderate correlation (R2 = 0.59). This MS-based assay can serve as an important tool in clinical studies aiming to elucidate the association between ApoE genotype, total ApoE, and ApoE isoform concentrations in various disorders related to ApoE polymorphisms. © 2014 American Chemical Society.
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| 3. |
- Martinez-Morillo, Eduardo, et al.
(author)
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Total apolipoprotein E levels and specific isoform composition in cerebrospinal fluid and plasma from Alzheimer's disease patients and controls
- 2014
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In: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 127:5, s. 633-643
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Journal article (peer-reviewed)abstract
- The apolipoprotein E (ApoE) epsilon 4 allele is the strongest risk factor of sporadic Alzheimer's disease (AD), however, the fluid concentrations of ApoE and its different isoforms (ApoE2, ApoE3 and ApoE4) in AD patients and among APOE genotypes (APOE epsilon 2, epsilon 3, epsilon 4) remain controversial. Using a novel mass spectrometry-based method, we quantified total ApoE and specific ApoE isoform concentrations and potential associations with age, cognitive status, cholesterol levels and established AD biomarkers in cerebrospinal fluid (CSF) from AD patients versus non-AD individuals with different APOE genotypes. We also investigated plasma total ApoE and ApoE isoform composition in a subset of these individuals. In total n = 43 AD and n = 43 non-AD subjects were included. We found that CSF and plasma total ApoE levels did not correlate with age or cognitive status and did not differ between AD and non-AD subjects deeming ApoE as an unfit diagnostic marker for AD. Also, whereas CSF ApoE levels did not vary between APOE genotypes APOE epsilon 4 carriers exhibited significantly decreased plasma ApoE levels attributed to a specific decrease in the ApoE4 isoform concentrations. CSF total ApoE concentrations were positively associated with CSF, total tau, tau phosphorylated at Thr181 and A beta 1-42 of which the latter association was weaker and only present in APOE epsilon 4 carriers indicating a differential involvement of ApoE in tau versus A beta-linked neuropathological processes. Future studies need to elucidate whether the observed plasma ApoE4 deficiency is a life-long condition in APOE E > 4 carriers and whether this decrease in plasma ApoE predisposes APOE E > 4 carriers to AD.
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| 4. |
- Nielsen, Henrietta, et al.
(author)
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Gender-dependent levels of hyaluronic acid in cerebrospinal fluid of patients with neurodegenerative dementia.
- 2012
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In: Current Alzheimer Research. - 1875-5828. ; 9:3, s. 257-266
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Journal article (peer-reviewed)abstract
- Numerous reports over the years have described neuroinflammatory events and vascular changes in neurodegenerative diseases such as Alzheimers disease (AD) and dementia with Lewy bodies (DLB). Interestingly, recent reports from other research areas suggest that the inflammatory and vascular processes are influenced by gender. These findings are intriguing from the perspective that women show a higher incidence of AD and warrant investigations on how gender influences various processes in neurodegenerative dementia. In the current study we measured the cerebrospinal fluid (CSF) and plasma concentrations of hyaluroinic acid (HA), an adhesionmolecule known to regulate both vascular and inflammatory processes, in AD and DLB patients as well as in healthy elders. Our analysis showed that male AD and DLB patients had almost double the amount of HA compared to female patients whereas no gender differences was observed in the controls. Furthermore, we found that CSF levels of HA in foremost female AD patients correlated with various AD related biomarkers. Correlations between HA levels and markers of inflammation and vascular changes were only detected in female AD patients but in both male and female DLB patients. We conclude that HA may be linked to several pathological events present in AD, as reflected in CSF protein concentrations. The HA profile in CSF, but not in plasma, and associations to other markers appear to be genderdependent which should be taken into account in clinical examinations and future biomarker studies.
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| 5. |
- Nielsen, Henrietta, et al.
(author)
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Low levels of soluble NG2 in cerebrospinal fluid from patients with dementia with Lewy bodies
- 2014
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In: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 40:2, s. 343-350
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Journal article (peer-reviewed)abstract
- The proteoglycan NG2 plays a major role in proliferation, migration, and differentiation of pericytes and NG2 cells in the brain. We have previously reported decreased soluble NG2 (sNG2) levels in cerebrospinal fluid (CSF) from patients with Alzheimer's disease (AD) and a relationship between sNG2 and AD biomarkers in these patients. To further investigate whether alterations in sNG2 is specific to AD pathology, we measured levels of sNG2 in CSF from a patient cohort consisting of non-demented controls (n = 51), patients with Parkinson's disease (PD) (n = 61), and patients with dementia with Lewy bodies (DLB) (n = 37), two synucleinopathies whereof the latter disorder frequently coincides with amyloid-β pathology similar to AD. We found decreased sNG2 concentrations in DLB patients, but not in PD patients, compared to controls. Levels of sNG2 in controls and PD patients correlated to T-tau, P-tau, α-synuclein, and neurosin. Only one correlation, between sNG2 and neurosin, was found in DLB patients. Analysis of a second cohort consisting of controls (n = 23) and DLB patients (n = 31) showed that the result was reproducible, as lower levels of sNG2 again were found in DLB patients compared to controls. We conclude that lower levels of sNG2 levels indicate a DLB-related impact on NG2 expressing cells foremost associated with neuropathology linked to accumulation of amyloid-β and not α-synuclein.
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| 6. |
- Nielsen, Henrietta, et al.
(author)
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NG2 cells, a new trail for Alzheimer's disease mechanisms?
- 2013
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In: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 1:1
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Journal article (peer-reviewed)abstract
- Neuron Glial 2 (NG2) cells are glial cells known to serve as oligodendrocyte progenitors as well as modulators of the neuronal network. Altered NG2 cell morphology and up-regulation as well as increased shedding of the proteoglycan NG2 expressed on the cell surface have been described in rodent models of brain injury. Here we describe alterations in the human NG2 cell population in response to pathological changes characteristic of Alzheimer's disease (AD).
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| 7. |
- Nielsen, Henrietta, et al.
(author)
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Plasma and CSF serpins in Alzheimer disease and dementia with Lewy bodies
- 2007
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In: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 1526-632X .- 0028-3878. ; 69, s. 1569-79
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Journal article (peer-reviewed)abstract
- ABSTRACT OBJECTIVE: Serine protease inhibitors (serpins), the acute phase reactants and regulators of the proteolytic processing of proteins, have been recognized as potential contributors to the pathogenesis of Alzheimer disease (AD). We measured plasma and CSF levels of serpins in controls and patients with dementia. METHODS: Using rocket immunoelectrophoresis, ELISA, and Luminex xMAP technology, we analyzed plasma levels of alpha1-antichymotrypsin and alpha1-antitrypsin, and CSF levels of alpha1-antichymotrypsin, alpha1-antitrypsin, and neuroserpin along with three standard biomarkers (total tau, tau phosphorylated at threonine-181, and the Abeta1-42) in patients with AD (n = 258), patients with dementia with Lewy bodies (DLB; n = 38), and age-matched controls (n = 37). RESULTS: The level of CSF neuroserpin was significantly higher in AD compared with controls and DLB, whereas CSF alpha1-antichymotrypsin and alpha1-antitrypsin were significantly higher in both AD and DLB groups than in controls. Results from logistic regression analyses demonstrate a relationship between higher CSF levels of alpha1-antichymotrypsin and neuroserpin and increased predicted probability and odds ratios (ORs) of AD (OR 5.3, 95% CI 1.3 to 20.8 and OR 3.3, CI 1.3 to 8.8). Furthermore, a logistic regression model based on CSF alpha1-antichymotrypsin, neuroserpin, and Abeta1-42 enabled us to discriminate between AD patients and controls with a sensitivity of 94.7% and a specificity of 77.8%. CONCLUSIONS: Higher CSF levels of neuroserpin and alpha1-antichymotrypsin were associated with the clinical diagnosis of Alzheimer disease (AD) and facilitated the diagnostic classification of AD vs controls. CSF serpin levels did not improve the diagnostic classification of AD vs dementia with Lewy bodies.
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| 8. |
- Nielsen, Henrietta, et al.
(author)
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Soluble adhesion molecules and angiotensin-converting enzyme in dementia.
- 2007
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In: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 26, s. 27-35
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Journal article (peer-reviewed)abstract
- We aimed to determine plasma and cerebrospinal fluid (CSF) levels of angiotensin-converting enzyme (ACE) and the soluble forms of intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1) and platelet endothelial cell adhesion molecule-1 (sPECAM-1) as surrogate markers for endothelial cell activation in clinically diagnosed patients with Alzheimer's disease (AD, n=260), dementia with Lewy bodies (DLB, n=39) and non-demented controls (n=34). Plasma sICAM-1 and sPECAM-1 were higher and CSF sVCAM-1 were lower in AD and DLB patients than in controls (p < 0.001). DLB patients had higher CSF sICAM-1, but lower CSF sVCAM-1 (p < 0.001). No difference in ACE levels was found between the dementia groups and controls. In controls and AD patients CSF sICAM and sVCAM-1 strongly correlated with each other and with blood barrier permeability whereas in DLB group these correlations were weaker. The observed patterns in adhesion molecules may reflect distinctions in the pathophysiological basis of their generation in dementia patients.
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| 9. |
- Patra, Kalicharan, et al.
(author)
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Assessment of kallikrein 6 as a cross-sectional and longitudinal biomarker for Alzheimer's disease
- 2018
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In: Alzheimer's Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 10
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Journal article (peer-reviewed)abstract
- Background: Kallikrein 6 (KLK6) is known to be an age-related protease expressed at high levels in the central nervous system. It was previously shown to be involved in proteolysis of extracellular proteins implicated in neurodegenerative diseases such as Alzheimer's disease (AD), prompting validation of KLK6 as a potential biomarker of disease. However, analyses of both plasma and cerebrospinal fluid (CSF) levels of KLK6 in patients with AD have been inconclusive. We present a detailed analysis of KLK6 in plasma and CSF in two separate cohorts in a cross-sectional and a longitudinal clinical setting. Methods: The cross-sectional cohort included control subjects without dementia and patients with AD, and the longitudinal cohort included patients with MCI and patients with AD followed over a 2-year period. Plasma and CSF levels of KLK6 were quantified by use of a previously developed and validated enzyme-linked immunosorbent assay. Statistical analyses were performed to compare KLK6 levels between diagnostic groups and to identify potential associations between KLK6 level, age, apolipoprotein E (APOE) genotype, total apoE level and the classical CSF AD biomarkers. Results: In the cross-sectional setting, KLK6 levels in plasma but not in CSF were significantly higher in the AD group than in control subjects. CSF but not plasma KLK6 levels were positively correlated with age in both the cross-sectional and longitudinal settings. In both cohorts, the CSF KLK6 levels were significantly and positively correlated with the CSF levels of core AD biomarkers. Total plasma and CSF apoE levels were positively associated with KLK6 in the cross-sectional study. Finally, during the 2-year monitoring period of the longitudinal cohort, CSF KLK6 levels increased with disease progression over time in the investigated patient groups. Conclusions: In two separate cohorts we have confirmed the previously reported correlation between age and CSF levels of KLK6. Increased plasma KLK6 levels in patients with AD with a more advanced disease stage suggest KLK6 as a potential biomarker in patients with AD with more severe dementia. Significant correlations between KLK6 levels and core CSF AD biomarkers suggest molecular links between KLK6 and AD-related pathological processes.
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| 10. |
- Schultz, Nina, et al.
(author)
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Involvement of Matrix Metalloproteinase-9 in Amyloid-β 1-42-Induced Shedding of the Pericyte Proteoglycan NG2.
- 2014
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In: Journal of Neuropathology and Experimental Neurology. - 1554-6578. ; 73:7, s. 684-692
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Journal article (peer-reviewed)abstract
- Deposition of amyloid-β (Aβ) 1-42, the major component of senile plaques characteristic of Alzheimer disease, affects brain microvascular integrity and causes blood-brain barrier dysfunction, increased angiogenesis, and pericyte degeneration. To understand the cellular events underlying Aβ1-42 effects on microvascular alterations, we investigated whether different aggregation forms of Aβ1-42 affect shedding of the pericyte proteoglycan NG2 and whether they affect proteolytic cleavage mediated by matrix metalloproteinase (MMP)-9. We found decreased levels of soluble NG2, total MMP-9, and MMP-9 activity in pericyte culture supernatants in response to fibril-enriched preparations of Aβ1-42. Conversely, oligomer-enriched preparations of Aβ1-42 increased soluble NG2 levels in the supernatants. This increase was ablated by the MMP-9/MMP-2 inhibitor SB-3CT. There was also a trend toward increased MMP-9 activity observed after oligomeric Aβ1-42 exposure. Our results, demonstrating an Aβ1-42 aggregation-dependent effect on levels of NG2 and MMP-9, support previous studies showing an impact of Aβ1-42 on vascular integrity and thereby add to our understanding of mechanisms behind the microvascular changes commonly found in patients with Alzheimer disease.
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