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Adenosine A2A receptors are putative therapeutic targets for neurological disorders. The adenosine A2A receptor antagonist istradefylline is approved in Japan for Parkinson’s disease and is being tested in clinical trials for this condition elsewhere. A2A receptors on neurons and astrocytes may contribute to Alzheimer’s disease (AD) by impairing memory. However, it is not known whether istradefylline enhances cognitive function in aging animals with or without AD-like amyloid plaque pathology. Here, we show that elevated levels of Aβ, C-terminal fragments of the amyloid precursor protein (APP), or amyloid plaques, but not overexpression of APP per se, increase astrocytic A2A receptor levels in the hippocampus and neocortex of aging mice. Moreover, in amyloid plaque-bearing mice, low-dose istradefylline treatment enhanced spatial memory and habituation, supporting the conclusion that, within a well-defined dose range, A2A receptor blockers might help counteract memory problems in patients with Alzheimer’s disease.

The quantification of microplastics (MP) in environmental samples is currently a challenging task. To enable low quantification limits, an analytical method has been developed combining pressurized liquid extraction (PLE) and pyrolysis GC-MS. The automated extraction includes a pre-extraction step via methanol followed by a subsequent PLE using tetrahydrofuran. For the most frequently used synthetic polymers polyethylene (PE), polypropylene (PP), and polystyrene (PS), limits of quantification were achieved down to 0.007 mg/g. Recoveries above 80% were attained for solid matrices such as soil and sediments. The developed method was applied for MP quantification in environmental samples such as sediment, suspended matter, soil, and sewage sludge. In all these matrices, PE and PP were detected with concentrations ranging from 0.03 to 3.3 mg/g. In sewage sludge samples, all three polymers were present with concentration levels ranging between 0.08 ± 0.02 mg/g (PP) and 3.3 ± 0.3 mg/g (PE). However, especially for solid samples, the analysis of triplicates revealed elevated statistical uncertainties due to the inhomogeneous distribution of MP particles. Thus, care has to be taken when milling and homogenizing the samples due to the formation of agglomerates. Graphical abstract.

Background In 2010 the spectrum of known antigens in autoimmune encephalitis has been expanded by GABAB receptors. Until now over 80 patients with GABAB receptor encephalitis have been described. We report the occurrence of GABAB receptor antibodies in a patient with clinically diagnosed amyotrophic lateral sclerosis (ALS). GABAB receptor antibodies have not been described previously in an ALS patient. Case presentation A 75-year-old female patient presented with cerebellar ataxia, bulbar palsy and cognitive impairment. In the later course of disease signs for affection of the second motor neuron evolved and she was diagnosed with ALS. A post-mortem analysis of cerebrospinal fluid revealed high titers of GABAB receptor antibodies. Conclusions This case provides an idea of the natural course of GABAB receptor encephalitis and demonstrates that antibody-mediated autoimmunity could be one of several pathways leading to the ALS phenotype. Furthermore this unique case stimulates the question whether neuronal antibodies might be more common in ALS than previously suspected.

Background In 2010 the spectrum of known antigens in autoimmune encephalitis has been expanded by GABAB receptors. Until now over 80 patients with GABAB receptor encephalitis have been described. We report the occurrence of GABAB receptor antibodies in a patient with clinically diagnosed amyotrophic lateral sclerosis (ALS). GABAB receptor antibodies have not been described previously in an ALS patient. Case presentation A 75-year-old female patient presented with cerebellar ataxia, bulbar palsy and cognitive impairment. In the later course of disease signs for affection of the second motor neuron evolved and she was diagnosed with ALS. A post-mortem analysis of cerebrospinal fluid revealed high titers of GABAB receptor antibodies. Conclusions This case provides an idea of the natural course of GABAB receptor encephalitis and demonstrates that antibody-mediated autoimmunity could be one of several pathways leading to the ALS phenotype. Furthermore this unique case stimulates the question whether neuronal antibodies might be more common in ALS than previously suspected. Electronic supplementary material The online version of this article (10.1186/s12883-019-1269-7) contains supplementary material, which is available to authorized users.

Myelin basic protein (MBP) is one of the most abundant proteins in the human brain. Active immunization with MBP induces experimental autoimmune encephalomyelitis, and anti-MBP antibodies have been repeatedly described in MS.1 However, its role in MS pathogenesis or prediction of disease progression is still unclear.2,3 Previous studies utilized enzyme-linked immunosorbent assay or immunoblot assays with linear epitopes of MBP, thus potentially overlooking autoantibodies that bind to MBP's natural conformation. These initial studies also included antibodies against another myelin protein, myelin oligodendrocyte glycoprotein (MOG). As happened for MBP, conflicting results stimulated the discussion of whether MOG antibodies contribute to MS pathogenesis.2,3 More recent work demonstrated that there are presumably pathogenic MOG antibodies defining the new entity of MOG antibody-associated disease;4 however, they bind to conformational MOG only. The authors are grateful to Professor Brian Popko, Department of Neurology, University of Chicago, for providing MBP knockout mouse brains.

The structural determination of peptide:HLA (human leucocyte antigen) class I complexes by X-ray crystallography has provided valuable information for understanding how peptides bind to individual HLA class I molecules and how this may influence the immune response. We compared 101 crystal structures of 9-mer peptide:HLA class I complexes available in the protein data bank (PDB) by performing a contact analysis using the Contact Map Analysis webserver http://ligin.weizmann.ac.il/cma. An InterSystems Cache ‘post-relational’ database containing residue position, amino acid (AA) and buried surface that contact a particular peptide position was then created allowing data comparison for all the structures (Pocketcheck). The analysis illustrates that the HLA class I residues 24, 45, 63 and 67 show high contact frequencies to both the p1 and/or p2 position of bound peptides, indicating that they might influence the nature of a peptide anchor. To determine the influence of these residues we utilized soluble HLA technology and mass spectrometry to analyze peptides derived from HLA-B*44:06 since it differs from the previously described allele B*44:02 by seven AA exchanges located in the alpha 1 domain (residues 24, 32, 41, 45, 63, 67 and 80). HLA-B*44:06 features an anchor motif of P or A at p2 and Y or W at the C-terminal. Additionally B*44:06-derived peptides feature an auxiliary anchor motif at p1, comprising D or E. Our results illustrate that structural analysis can provide valuable information to understand allogenicity and provides a further step towards intelligent HLA mismatching.

Tumor necrosis factor-α is assumed to be an important mediator in thyroid autoimmunity. In the present study we have shown that human thyrocytes possess a single specific binding site for recombinant tumor necrosis factor-α with an average of 9,300 receptors/cell (Kd = 1.9 · 10−10 mol). The effects of the cytokine on thyroid cell proliferation were assessed by 3H-thymidine uptake as well as by the protein and DNA content of cell monolayers. Low dose tumor necrosis factor-α resulted in a moderate stimulation of cell proliferation with an increase of 3H-thymidine incorporation from 44,613±7,989 cpm under basal conditions to 63,326±6,822 cpm after 100 U/l tumor necrosis factor-α (p

Aim Defining permissive and non-permissive mismatches for transplantation is a walk on a tightrope. Knowledge about the magnitude of individual polymorphism is a critical part in understanding the complexity of comprehensive mismatching. HLA-B ∗ 44:09 differs from the highly frequent B ∗ 44:02 by polymorphisms at residues 77, 80, 81, 82 and 83. We aimed to identify the magnitude of these mismatches on the features of B ∗ 44:09 bound peptides since residues 77, 80 and 81 comprise part of pocket F. Methods Using soluble HLA technology we determined >200 individual self peptides from B ∗ 44:09 and compared their features with that of B ∗ 44:02. To understand the structural basis for the B ∗ 44:09 pΩ anchor we generated a molecular model of B ∗ 44:09 based on the structure of B ∗ 44:02 (3L3D). Results Both alleles illustrate an E at p2. In contrast to the C-terminal peptide binding motif of B ∗ 44:02 (W, F, Y or L), B ∗ 44:09 derived peptides are restricted predominantly to L or F. We identify 23 shared peptides that contained the restricted B ∗ 44:09 anchor motif of F or L at the pΩ position. Residues 77, 80 and 81 are known to be part of pocket F, while residues 82 and 83 lie on the periphery of the PBR and are not involved in peptide binding. Structurally 77 and 80 make contact with the peptide main chain at pΩ, while residue 81 contacts the pΩ side chain. However, residue 81Leu (B ∗ 44:09) appears to be the main cause of pΩ sequence specificity by restricting the size of the F pocket, resulting its in selection against a bulky residue such as W. Conclusions These results highlight that every amino acid substitution has an impact of certain magnitude on the alleles function and demonstrate how surrounding residues orchestrate peptide specificity. Peptide motif based ranking of allelic mismatches can contribute to the donor selection process when no HLA-identical donor is available to prevent mismatching being a matter of chance.

Apomorphine is known to improve the retention performance of a brightness discrimination task after post-training intrahippocampal application to rats. The present study shows that the retention performance of dopamine supersensitive rats was improved by a low dose of apomorphine which was still ineffective in control animals. Dopamine supersensitivity by itself had no effect on acquisition and retention parameters of brightness discrimination. The result further supports the assumption that dopamine receptors in rat hippocampus can modulate the formation of memory.