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A novel sandwich-type photoelectrochemical immunosensor based on Ru(bpy)32+ and Ce-CdS co-sensitized hierarchical ZnO matrix and dual-inhibited polystyrene@CuS-Ab2 composites.
Fan, D, Liu, X, Bao, C, Feng, J, Wang, H, Ma, H, Wu, D, Wei, Q
Biosensors & bioelectronics. 2019;:124-131
Abstract
A novel and sensitive sandwich-type photoelectrochemical (PEC) immunosensor was developed for the quantitative detection of β-amyloid protein (Aβ). A ITO electrode was sequentially coated with hierarchical porous zinc oxide (ZnO) microspheres with a large specific area, sensitized with tris(bipyridine)ruthenium(II) ion (Ru(bpy)32+) to achieve high visible light absorption, and modified with cerium-doped cadmium sulfide (Ce-CdS) nanoparticles to enhance the PEC response. Under the stimulation of visible light and ascorbic acid as an efficient electron donor, the photoelectric signal of ZnO/Ru(bpy)32+/Ce-CdS was 70 times that of pure ZnO. The amino-functionalized polystyrene (PS) microspheres coated with copper sulfide (CuS) was linked with a secondary antibody (Ab2) for the first time for the Aβ detection by the immunosensor. The good insulation and steric resistance of the as-prepared polystyrene@CuS-Ab2 (PS@CuS-Ab2) composite significantly weakened the photocurrent response of the immunosensor in the specific immune recognition. Under the optimal conditions, the quantitative detection of Aβ was achieved within the range of 0.001-100 ng/mL with the detection limit of 0.37 pg/mL. In addition, the PEC immunosensor is easy to make, stable and selective, which has provided a good experimental platform for the detection of disease biomarkers.
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Safety, tolerability and immunogenicity of an active anti-Aβ40 vaccine (ABvac40) in patients with Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase I trial.
Lacosta, AM, Pascual-Lucas, M, Pesini, P, Casabona, D, Pérez-Grijalba, V, Marcos-Campos, I, Sarasa, L, Canudas, J, Badi, H, Monleón, I, et al
Alzheimer's research & therapy. 2018;(1):12
Abstract
BACKGROUND Immunotherapy targeting the amyloid-β (Aβ) peptide is a promising strategy for the treatment of Alzheimer's disease (AD); however, none of the active or passive vaccines tested have been demonstrated to be effective to date. We have developed the first active vaccine against the C-terminal end of Aβ40, ABvac40, and assessed its safety and tolerability in a phase I clinical trial. METHODS A randomised, double-blind, placebo-controlled, parallel-group, phase I study of ABvac40 was conducted with patients aged 50-85 years with mild to moderate AD. Participants were entered into three separate groups according to time of study entry and were randomly allocated to receive ABvac40 or placebo (overall ratio 2:1). The first group received two half-doses of ABvac40 or placebo, whereas the second and third groups received two and three full doses, respectively. All treatments were administered subcutaneously at 4-week intervals. Patients, carers and investigators were blind to treatment allocation throughout the study. The primary objective was to assess the safety and tolerability of ABvac40 by registering all adverse events (AEs). All patients who received at least one dose of treatment were included in the safety analysis. The secondary objective was to evaluate the immunogenicity of ABvac40 by titration of specific anti-Aβ40 antibodies in plasma. RESULTS Twenty-four patients were randomly allocated: 16 patients to the ABvac40 group and 8 patients to the placebo group. All randomised patients completed the study, therefore the intention-to-treat and safety populations were identical. Overall, 71 AEs affecting 18 patients were recorded: 11 (69%) in the ABvac40 group and 7 (88%) in the placebo group (p = 0.6214). Neither incident vasogenic oedema nor sulcal effusion (amyloid-related imaging abnormalities corresponding to vasogenic oedema and sulcal effusions) nor microhaemorrhages (amyloid-related imaging abnormalities corresponding to microhaemorrhages and hemosiderin deposits) were detected throughout the study period in the ABvac40-treated patients. Eleven of 12 (~92%) individuals receiving three injections of ABvac40 developed specific anti-Aβ40 antibodies. CONCLUSIONS ABvac40 showed a favourable safety and tolerability profile while eliciting a consistent and specific immune response. An ongoing phase II clinical trial is needed to confirm these results and to explore the clinical efficacy of ABvac40. TRIAL REGISTRATION ClinicalTrials.gov, NCT03113812 . Retrospectively registered on 14 April 2017.
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Amyloid-Like β-Aggregates as Force-Sensitive Switches in Fungal Biofilms and Infections.
Lipke, PN, Klotz, SA, Dufrene, YF, Jackson, DN, Garcia-Sherman, MC
Microbiology and molecular biology reviews : MMBR. 2018;(1)
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Abstract
Cellular aggregation is an essential step in the formation of biofilms, which promote fungal survival and persistence in hosts. In many of the known yeast cell adhesion proteins, there are amino acid sequences predicted to form amyloid-like β-aggregates. These sequences mediate amyloid formation in vitro. In vivo, these sequences mediate a phase transition from a disordered state to a partially ordered state to create patches of adhesins on the cell surface. These β-aggregated protein patches are called adhesin nanodomains, and their presence greatly increases and strengthens cell-cell interactions in fungal cell aggregation. Nanodomain formation is slow (with molecular response in minutes and the consequences being evident for hours), and strong interactions lead to enhanced biofilm formation. Unique among functional amyloids, fungal adhesin β-aggregation can be triggered by the application of physical shear force, leading to cellular responses to flow-induced stress and the formation of robust biofilms that persist under flow. Bioinformatics analysis suggests that this phenomenon may be widespread. Analysis of fungal abscesses shows the presence of surface amyloids in situ, a finding which supports the idea that phase changes to an amyloid-like state occur in vivo. The amyloid-coated fungi bind the damage-associated molecular pattern receptor serum amyloid P component, and there may be a consequential modulation of innate immune responses to the fungi. Structural data now suggest mechanisms for the force-mediated induction of the phase change. We summarize and discuss evidence that the sequences function as triggers for protein aggregation and subsequent cellular aggregation, both in vitro and in vivo.
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Neuroinflammation, immune system and Alzheimer disease: searching for the missing link.
Guerriero, F, Sgarlata, C, Francis, M, Maurizi, N, Faragli, A, Perna, S, Rondanelli, M, Rollone, M, Ricevuti, G
Aging clinical and experimental research. 2017;(5):821-831
Abstract
Due to an increasingly aging population, Alzheimer disease (AD) represents a crucial issue for the healthcare system because of its widespread prevalence and the burden of its care needs. Several hypotheses on AD pathogenesis have been proposed and current therapeutical strategies have shown limited effectiveness. In the last decade, more evidence has supported a role for neuroinflammation and immune system dysregulation in AD. It remains unclear whether astrocytes, microglia and immune cells influence disease onset, progression or both. Amyloid-β peptides that aggregate extracellularly in the typical neuritic plaques generate a constant inflammatory environment. This causes a prolonged activation of microglial and astroglial cells that potentiate neuronal damage and provoke the alteration of the blood brain barrier (BBB), damaging the permeability of blood vessels. Recent data support the role of the BBB as a link between neuroinflammation, the immune system and AD. Hence, a thorough investigation of the neuroinflammatory and immune system pathways that impact neurodegeneration and novel exciting findings such as microglia-derived microvesicles, inflammasomes and signalosomes will ultimately enhance our understanding of the pathological process. Eventually, we should proceed with caution in defining a causal or consequential role of neuroinflammation in AD, but rather focus on identifying its exact pathological contribution.