| 261. |
- Westman, Gabriel, et al.
(author)
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Application of a Multiplex Herpesvirus Immunoassay in Alzheimer’s Disease
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Other publication (other academic/artistic)abstract
- Human herpesviruses have previously been implicated in the pathogenesis of Alzheimer's disease (AD) but whether they are causal, facilitating or confounding factors is yet to be established. Here, we present an application of a suspension matrix immunoassay (SMIA) allowing multiplex detection of IgG levels related to five human herpesviruses. Furthermore, we analysed peripheral blood mononuclear cells with a subtype specific HHV-6 PCR. The level of HHV-6 antibodies was lower in AD subjects (n=51) than in non-demented controls (ND, n=52), whereas there were no differences in HSV, VZV, CMV or EBV antibody levels between groups. AD and ND subjects presented with comparable DNA levels in PBMC and all positive samples were of subtype B. The SMIA protocol, applied to herpesvirus antigens, could provide an useful addition to the scientific arsenal. Whether HHV-6 is a factor in AD remains a hypothesis for future studies.
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| 262. |
- Westman, Gabriel, et al.
(author)
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Decreased HHV-6 IgG in Alzheimer's Disease
- 2017
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In: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 8
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Journal article (peer-reviewed)abstract
- Human herpesviruses have previously been implicated in the pathogenesis of Alzheimer's disease (AD) but whether they are causal, facilitating, or confounding factors is yet to be established. A total of 50 AD subjects and 52 non-demented (ND) controls were analyzed in a multiplex assay for IgG reactivity toward herpes simplex virus (HSV), varicella zoster virus (VZV), cytomegalovirus (CMV), and human herpesvirus 6 (HHV-6). The HHV-6 IgG reactivity was significantly lower in AD subjects compared to ND controls, whereas there were no differences in HSV, VZV, or CMV antibody levels between the groups. Analysis of peripheral blood mononuclear cells with a subtype-specific HHV-6 PCR revealed no signs of reactivation, as AD and ND subjects presented with comparable HHV-6 DNA levels in PBMCs, and all positive samples were of subtype B. Whether HHV-6 is a factor in AD remains to be elucidated in future studies.
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| 263. |
- Westman, Gabriel, et al.
(author)
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Decreased Proportion of Cytomegalovirus Specific CD8 T-Cells but No Signs of General Immunosenescence in Alzheimer's Disease
- 2013
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:10, s. e77921-
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Journal article (peer-reviewed)abstract
- Cytomegalovirus (CMV) has been suggested as a contributing force behind the impaired immune responsiveness in the elderly, with decreased numbers of naive T-cells and an increased proportion of effector T-cells. Immunological impairment is also implicated as a part of the pathogenesis in Alzheimer's disease (AD). The aim of this study was to investigate whether AD patients present with a different CMV-specific CD8 immune profile compared to non-demented controls. Blood samples from 50 AD patients and 50 age-matched controls were analysed for HLA-type, CMV serostatus and systemic inflammatory biomarkers. Using multi-colour flow cytometry, lymphocytes from peripheral blood mononuclear cells were analysed for CMV-specific CD8 immunity with MHC-I tetramers A01, A02, A24, B07, B08 and B35 and further classified using CD27, CD28, CD45RA and CCR7 antibodies. Among CMV seropositive subjects, patients with AD had significantly lower proportions of CMV-specific CD8 T-cells compared to controls, 1.16 % vs. 4.13 % (p=0.0057). Regardless of dementia status, CMV seropositive subjects presented with a lower proportion of naive CD8 cells and a higher proportion of effector CD8 cells compared to seronegative subjects. Interestingly, patients with AD showed a decreased proportion of CMV-specific CD8 cells but no difference in general CD8 differentiation.
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| 264. |
- Westman, Gabriel, et al.
(author)
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Increased Inflammatory Response in Cytomegalovirus Seropositive Patients with Alzheimer's Disease
- 2014
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:5, s. e96779-
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Journal article (peer-reviewed)abstract
- Alzheimer's disease (AD) has been associated with increased local inflammation in the affected brain regions, and in some studies also with elevated levels of proinflammatory cytokines in peripheral blood. Cytomegalovirus (CMV) is known to promote a more effector-oriented phenotype in the T-cell compartment, increasing with age. The aim of this study was to investigate the inflammatory response of peripheral blood mononuclear cells (PBMCs) from AD patients and non-demented (ND) controls. Using a multiplex Luminex xMAP assay targeting GM-CSF, IFN-gamma, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-8, IP-10 and TNF-alpha, cytokine profiles from PBMCs were analysed after stimulation with anti-CD3/CD28 beads, CMV pp65 peptide mix or amyloid beta (A beta) protofibrils, respectively. CMV seropositive AD subjects presented with higher IFN-gamma levels after anti-CD3/ CD28 and CMV pp65 but not after Ab stimulation, compared to CMV seropositive ND controls. When analysing IFN-gamma response to anti-CD3/CD28 stimulation on a subgroup level, CMV seropositive AD subjects presented with higher levels compared to both CMV seronegative AD and CMV seropositive ND subjects. Taken together, our data from patients with clinically manifest AD suggest a possible role of CMV as an inflammatory promoter in AD immunology. Further studies of AD patients at earlier stages of disease, could provide better insight into the pathophysiology.
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| 265. |
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| 266. |
- Wiberg, Henning, et al.
(author)
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Separation and characterization of aggregated species of amyloid-beta peptides
- 2010
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In: Analytical and Bioanalytical Chemistry. - : Springer Science and Business Media LLC. - 1618-2642 .- 1618-2650. ; 397:6, s. 2357-2366
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Journal article (peer-reviewed)abstract
- We have investigated the use of isoelectric focusing and immunodetection for the separation of low molecular weight species of amyloid-beta (A beta) peptides from their aggregates. From solutions of A beta(1-40) or A beta(1-42) monomeric peptides, low molecular weight material appeared at a pI value of ca. 5, while the presence of aggregates was detected as bands, observed at a pI of 6-6.5. The formation of A beta aggregates (protofibrils) was verified by a sandwich ELISA, employing the protofibril conformation-selective antibody mAb158. In order to study the aggregation behavior when using a mixture of the monomers, we utilized the IEF separation combined with Western blot using two polyclonal antisera, selective for A beta(1-40) and A beta(1-42), respectively. We conclude that both monomers were incorporated in the aggregates. In a further study of the mixed aggregates, we used the protofibril conformation-selective antibody mAb158 for immunoprecipitation, followed by nanoelectrospray mass spectrometry (IP-MS). This showed that the A beta(1-42) peptide is incorporated in the aggregate in a significantly larger proportion than its relative presence in the original monomer composition. IP-MS with mAb158 was also performed, and compared to IP-MS with the A beta-selective antibody mAb1C3, where a monomeric A beta(1-16) peptide was added to the protofibril preparation. A beta(1-16) is known for its poor aggregation propensity, and acted therefore as a selectivity marker. The results obtained confirmed the protofibril conformation selectivity of mAb158.
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| 267. |
- Wiig, E H, et al.
(author)
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The stability of AQT processing speed, ADAS-Cog and MMSE during acetylcholinesterase inhibitor treatment in Alzheimer's disease
- 2010
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In: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314 .- 1600-0404. ; 121:3, s. 186-193
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Journal article (peer-reviewed)abstract
- OBJECTIVES: To explore the longitudinal stability of measures of cognition during treatment with acetylcholinesterase inhibitors (AchEI) in patients with Alzheimer's disease (AD). MATERIALS AND METHODS: Cognitive status was measured in a cohort of 60 patients at 6 months after initiation of treatment with AchEI (baseline) and after an additional 6 months of treatment (endpoint). A Quick Test of Cognitive Speed (AQT), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and MMSE were administered concurrently. RESULTS: Correlations (rho) between age and AQT processing speed were non-significant, but were significant for ADAS-Cog and Mini Mental State Examination (MMSE). AQT and ADAS-Cog means did not differ significantly between baseline and endpoint. There was a small, significant reduction in MMSE point scores. Measures of stability (Spearman's rho) were moderate-to-high for all tests. Means for subgroups did not differ as a function of medication type. CONCLUSIONS: AQT processing speed, ADAS-Cog, and MMSE measures proved stable during the second 6 months of treatment with AChEI.
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| 268. |
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| 269. |
- Willem, Michael, et al.
(author)
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eta-Secretase processing of APP inhibits neuronal activity in the hippocampus
- 2015
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 526:7573, s. 443-447
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Journal article (peer-reviewed)abstract
- Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-beta peptide(1). Two principal physiological pathways either prevent or promote amyloid-beta generation from its precursor, beta-amyloid precursor protein (APP), in a competitive manne(r)1. Although APP processing has been studied in great detail, unknown proteolytic events seem to hinder stoichiometric analyses of APP metabolism in vivo(2). Here we describe a new physiological APP processing pathway, which generates proteolytic fragments capable of inhibiting neuronal activity within the hippocampus. We identify higher molecular mass carboxy-terminal fragments (CTFs) of APP, termed CTF-eta, in addition to the long-known CTF-alpha and CTF-beta fragments generated by the alpha- and beta-secretases ADAM10 (a disintegrin and metalloproteinase 10) and BACE1 (beta-site APP cleaving enzyme 1), respectively. CTF-eta generation is mediated in part by membrane-bound matrix metalloproteinases such as MT5-MMP, referred to as g-secretase activity. g-Secretase cleavage occurs primarily at amino acids 504-505 of APP(695), releasing a truncated ectodomain. After shedding of this ectodomain, CTF-eta is further processed by ADAM10 and BACE1 to release long and short A eta peptides (termed A eta-alpha and A eta-beta). CTFs produced by g-secretase are enriched in dystrophic neurites in an AD mouse model and in human AD brains. Genetic and pharmacological inhibition of BACE1 activity results in robust accumulation of CTF-eta and A eta-alpha. In mice treated with a potent BACE1 inhibitor, hippocampal long-term potentiation was reduced. Notably, when recombinant or synthetic A eta-alpha was applied on hippocampal slices ex vivo, long-term potentiation was lowered. Furthermore, in vivo single-cell two-photon calcium imaging showed that hippocampal neuronal activity was attenuated by A eta-alpha. These findings not only demonstrate a major functionally relevant APP processing pathway, but may also indicate potential translational relevance for therapeutic strategies targeting APP processing.
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| 270. |
- Wiltfang, J., et al.
(author)
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Consensus Paper of the WFSBP Task Force on Biological Markers of Dementia : The role of CSF and blood analysis in the early and differential diagnosis of dementia
- 2009
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In: Revista de Psiquiatria Clinica. - 0101-6083. ; 36, s. 1-16
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Research review (peer-reviewed)abstract
- Aging of population, and increasing life expectancy result in an increasing number of patients with dementia. This symptom can be a part of a completely curable disease of the central nervous system (e.g, neuroinflammation), or a disease currently considered irreversible (e.g, Alzheimer's disease, AD). In the latter case, several potentially successful treatment approaches are being tested now, demanding reasonable standards of pre-mortem diagnosis. Cerebrospinal fluid and serum analysis (CSF/serum analysis), whereas routinely performed in neuroinflammatory diseases, still requires standardization to be used as an aid to the clinically based diagnosis of AD. Several AD-related CSF parameters (total tau, phosphorylated forms of tau, A beta peptides, ApoE genotype, p97, etc.) tested separately or in a combination provide sensitivity and specificity in the range of 85%, the figure commonly expected from a good diagnostic tool. In this review, recently published reports regarding progress in neurochemical pre-mortem diagnosis of dementias are discussed with a focus on an early and differential diagnosis of AD. Novel perspectives offered by recently introduced technologies, e.g, fluorescence correlation spectroscopy (FCS) and surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) are briefly discussed.
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