| 1. |
- Barrantes, Alejandro, et al.
(författare)
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Alzheimer’s Disease Amyloid Peptides Interact with DNA, As Proved by Surface Plasmon Resonance
- 2012
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Ingår i: Current Alzheimer Research. - : Bentham eBooks. - 1567-2050 .- 1875-5828. ; 9:8, s. 924-934
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Tidskriftsartikel (refereegranskat)abstract
- According to the amyloid hypothesis, abnormal processing of the β-amyloid precursor protein in Alzheimer's disease patients increases the production of β-amyloid toxic peptides, which, after forming highly aggregated fibrillar structures, lead to extracellular plaques formation, neuronal loss and dementia. However, a great deal of evidence has point to intracellular small oligomers of amyloid peptides, probably transient intermediates in the process of fibrillar structures formation, as the most toxic species. In order to study the amyloid-DNA interaction, we have selected here three different forms of the amyloid peptide: Aβ1-40, Aβ25-35 and a scrambled form of Aβ25-35. Surface Plasmon Resonance was used together with UV-visible spectroscopy, Electrophoresis and Electronic Microscopy to carry out this study. Our results prove that, similarly to the full length Aβ1-42, all conformations of toxic amyloid peptides, Aβ1-40 and Aβ25-35, may bind DNA. In contrast, the scrambled form of Aβ25-35, a non-aggregating and nontoxic form of this peptide, could not bind DNA. We conclude that although the amyloid-DNA interaction is closely related to the amyloid aggregation proneness, this cannot be the only factor which determines the interaction, since small oligomers of amyloid peptides may also bind DNA if their predominant negatively charged amino acid residues are previously neutralized.
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| 2. |
- Chakrabarti, Sankha Shubhra, et al.
(författare)
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Ceramide and Sphingosine-1-Phosphate in Cell Death Pathways: Relevance to the Pathogenesis of Alzheimers Disease
- 2016
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Ingår i: Current Alzheimer Research. - : BENTHAM SCIENCE PUBL LTD. - 1567-2050 .- 1875-5828. ; 13:11, s. 1232-1248
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Forskningsöversikt (refereegranskat)abstract
- The metabolic turnover of sphingolipids produces several signaling molecules that profoundly affect the proliferation, differentiation and death of cells. In particular, an enormous body of information is available that defines the varied role of ceramide and sphingosine-1-phosphate in cell death and survival. This review specifically examines the role of ceramide and sphingosine-1-phosphate in triggering neuronal death in Alzheimers disease by analyzing the data from post-mortem studies and experimental research. There is compelling evidence that ceramide plays a key role in the neurodegeneration and amyloidogenesis occurring in the brain in Alzheimers disease. Further, it appears that ceramide and amyloid beta protein orchestrate an attack on mitochondria to set in the pathways of cell death. However, the complexity of metabolic and signaling pathways of sphingolipid derivatives precludes an immediate identification of effective drug targets for the therapy of Alzheimers disease.
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| 5. |
- Forsberg, A, et al.
(författare)
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High PIB Retention in Alzheimer's Disease is an Early Event with Complex Relationship with CSF Biomarkers and Functional Parameters
- 2010
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Ingår i: Current Alzheimer Research. - : Bentham Science Publishers Ltd.. - 1567-2050 .- 1875-5828. ; 7:1, s. 56-66
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Tidskriftsartikel (refereegranskat)abstract
- Background:New in vivo amyloid PET imaging tracers, such as 11C-PIB, provide possibilities to deeper understand the underlying pathological processes in Alzheimers disease (AD). In this study we investigated how 11C-PIB retention is related to cerebral glucose metabolism, episodic memory and CSF biomarkers.Method:Thirty-seven patients with mild AD and 21 patients with mild cognitive impairment (MCI) underwent PET examinations with the amyloid tracer 11C-PIB, 18F-FDG for measurement of regional cerebral metabolic rate of glucose (rCMRglc), assessment of episodic memory and assay of cerebral spinal fluid (CSF) levels of amyloid-ß (Aβ1-42), total tau and phosphorylated tau respectively. Analyses were performed using Statistical Parametric Mapping (SPM) and regions of interest (ROIs).Results:Pooled data from AD and MCI patients showed strong correlations between 11C-PIB retention, levels of CSF biomarkers (especially Aß1-42), rCMRglc and episodic memory. Analysis of the MCI group alone revealed significant correlations between 11C-PIB retention and CSF biomarkers and between CSF biomarkers and episodic memory respectively. A strong correlation was observed in the AD group between rCMRglc and episodic memory as well as a significant correlation between 11C-PIB retention and rCMRglc in some cortical regions. Regional differences were observed as sign for changes in temporal patterns across brain regions.Conclusions:A complex pattern was observed between pathological and functional markers with respect to disease stage (MCI versus AD) and brain regions. Regional differences over time were evident during disease progression. 11C-PIB PET and CSF Aß1-42 allowed detection of prodromal stages of AD. Amyloid imaging is useful for early diagnosis and evaluation of new therapeutic interventions in AD.
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| 6. |
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| 7. |
- Hall, Anette, et al.
(författare)
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Predicting Progression from Cognitive Impairment to Alzheimer's Disease with the Disease State Index
- 2015
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Ingår i: Current Alzheimer Research. - : Bentham Science Publishers Ltd.. - 1875-5828 .- 1567-2050. ; 12:1, s. 69-79
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated the performance of the Disease State Index (DSI) method when predicting progression to Alzheimer's disease (AD) in patients with subjective cognitive impairment (SCI), amnestic or non-amnestic mild cognitive impairment (aMCI, naMCI). The DSI model measures patients' similarity to diagnosed cases based on available data, such as cognitive tests, the APOE genotype, CSF biomarkers and MRI. We applied the DSI model to data from the DE-SCRIPA cohort, where non-demented patients (N=775) with different subtypes of cognitive impairment were followed for 1 to 5 years. Classification accuracies for the subgroups were calculated with the DSI using leave-one-out cross-validation. The DSI's classification accuracy in predicting progression to AD was 0.75 (AUC=0.83) in the total population, 0.70 (AUC=0.77) for aMCI and 0.71 (AUC=0.76) for naMCI. For a subset of approximately half of the patients with high or low DSI values, accuracy reached 0.86 (all), 0.78 (aMCI), and 0.85 (naMCI). For patients with MRI or CSF biomarker data available, they were 0.78 (all), 0.76 (aMCI) and 0.76 (naMCI), while for clear cases the accuracies rose to 0.90 (all), 0.83 (aMCI) and 0.91 (naMCI). The results show that the DSI model can distinguish between clear and ambiguous cases, assess the severity of the disease and also provide information on the effectiveness of different biomarkers. While a specific test or biomarker may confound analysis for an individual patient, combining several different types of tests and biomarkers could be able to reveal the trajectory of the disease and improve the prediction of AD progression.
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| 8. |
- Herrmann, Francois R., et al.
(författare)
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Determinants of Cognitive Trajectories in Normal Aging : A Longitudinal PET-MRI Study in a Community-based Cohort
- 2021
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Ingår i: Current Alzheimer Research. - : Bentham Science Publishers. - 1567-2050 .- 1875-5828. ; 18:6, s. 482-491
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Tidskriftsartikel (refereegranskat)abstract
- Background: The determinants of the progressive decrement of cognition in normal aging are still a matter of debate. Alzheimer disease (AD)-signature markers and vascular lesions, but also psychological variables such as personality factors, are thought to have an impact on the longitudinal trajectories of neuropsychological performances in healthy elderly individuals.Objective: The current research aimed to identify the main determinants associated with cognitive trajectories in normal aging.Methods: We performed a 4.5-year longitudinal study in 90 older community-dwellers coupling two neuropsychological assessments, medial temporal atrophy (MTA), number of cerebral microbleeds (CMB), and white matter hyperintensities (WMH) at inclusion, visual rating of amyloid and FDG PET at follow-up, and APOE genotyping. Personality factors were assessed at baseline using the NEO-PIR. Univariate and backward stepwise regression models were built to explore the association between the continuous cognitive score (CCS) and both imaging and personality variables.Results: The number of strictly lobar CMB at baseline (4 or more) was related to a significant increase in the risk of cognitive decrement. In multivariable models, amyloid positivity was associated with a 1.73 unit decrease of the CCS at follow-up. MTA, WMH and abnormal FDG PET were not related to the cognitive outcome. Among personality factors, only higher agreeableness was related to better preservation of neuropsychological performances.Conclusion: CMB and amyloid positivity are the only imaging determinants of cognitive trajectories in this highly selected series of healthy controls. Among personality factors, higher agreeableness confers a modest but significant protection against the decline of cognitive performances.
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| 9. |
- Jaremo, Petter, et al.
(författare)
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Alzheimers Disease: Erythrocyte 2,3-diphosphoglycerate Content and Circulating Erythropoietin
- 2019
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Ingår i: Current Alzheimer Research. - : BENTHAM SCIENCE PUBL LTD. - 1567-2050 .- 1875-5828. ; 16:9, s. 834-835
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimers Disease (AD) features the accumulation of beta-amyloid in erythrocytes. The subsequent red cell damage may well affect their oxygen-carrying capabilities. 2,3-diphosphoglycerate (2,3-DPG) binds to the hemoglobin thereby promoting oxygen release. It is theorized that 2,3-DPG is reduced in AD and that the resulting hypoxia triggers erythropoietin (EPO) release. Methods amp; Objective: To explore this theory, we analyzed red cell 2,3-DPG content and EPO in AD, mild cognitive impairment, and the control group, subjective cognitive impairment. Results: We studied (i) 2,3-DPG in red cells, and (ii) circulating EPO in AD, and both markers were unaffected by dementia. Disturbances of these oxygen-regulatory pathways do not appear to participate in brain hypoxia in AD.
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| 10. |
- Jaremo, Petter, et al.
(författare)
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Erythrocyte Amyloid Beta Peptide Isoform Distributions in Alzheimer and Mild Cognitive Impairment
- 2019
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Ingår i: Current Alzheimer Research. - : BENTHAM SCIENCE PUBL LTD. - 1567-2050 .- 1875-5828. ; 16:11, s. 1050-1054
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: We recently showed that Amyloid Beta (A beta)(40) accumulates in erythrocytes and possibly causes cell damage as evidenced by an increased number of assumed injured low-density (kg/L) erythrocytes. Furthermore, we have suggested a separation technique to isolate and concentrate such damaged red blood cells for subsequent analysis. Objectives: We isolated high- and low-density erythrocytes and investigated the accumulation patterns of the A beta peptides (A beta(40), A beta(42), and A beta(43) ) in Alzheimer (AD), mild cognitive impairment (MCI), and Subjective Cognitive Impairment (SCI). Methods: Whole blood was fractionated through a density gradient, resulting in two concentrated high-and presumed injured low-density erythrocyte fractions. After cell lysis, intracellular A beta(40) , A beta 4(2), and A beta (43) were quantified by ELISA. Results: In both high- and low-density erythrocytes, A beta(40) displayed the lowest concentration in MCI, while it was equal and higher in AD and SCI. A beta(40) was detected at a 10-fold higher level than A beta(42), and in injured low-density erythrocytes, the lowest quantity of A beta(42) was found in AD and MCI. A beta(40) exhibited a 100-fold greater amount than A beta(43). and lighter erythrocytes of MCI subjects displayed less intracellular A beta(43) than SCI. Conclusion: Red blood cell accumulation patterns of A beta(40), A beta(42), and A beta(43) differ significantly between AD, MCI, and SCI. The data must be verified through larger clinical trials. It is, however, tenable that AP peptide distributions in erythrocyte subpopulations have the potential to be used for diagnostic purposes.
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