A5064065407- Alzheimer's disease research and treatments
- Amino Acid Enzymes and Metabolism
- Neuroscience and Neuropharmacology Research
- Glycosylation and Glycoproteins Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Chromosomal and Genetic Variations
- Peptidase Inhibition and Analysis
- 14-3-3 protein interactions
- Computational Drug Discovery Methods
- Chemokine receptors and signaling
- Cholinesterase and Neurodegenerative Diseases
- CRISPR and Genetic Engineering
- Metabolism and Genetic Disorders
- Genomics and Phylogenetic Studies
- Prion Diseases and Protein Misfolding
- Protein Hydrolysis and Bioactive Peptides
- Tryptophan and brain disorders
- Immune cells in cancer
- Endoplasmic Reticulum Stress and Disease
- Polyamine Metabolism and Applications
- Neuropeptides and Animal Physiology
- Protease and Inhibitor Mechanisms
- Supramolecular Self-Assembly in Materials
- Liver physiology and pathology
- Biochemical Acid Research Studies
Fraunhofer Institute for Cell Therapy and Immunology
2014-2024
Martin Luther University Halle-Wittenberg
2024
Probiodrug (Germany)
2005-2017
Brigham and Women's Hospital
2013-2016
Harvard University
2013-2016
Fraunhofer Society
2014-2015
RIKEN Center for Brain Science
2008
It is well established that only a fraction of Abeta peptides in the brain Alzheimer's disease (AD) patients start with N-terminal aspartate (Abeta(1D)) which generated by proteolytic processing amyloid precursor protein (APP) BACE. N-terminally truncated and pyroglutamate modified starting at position 3 ending amino acid 42 [Abeta(3(pE)-42)] have been previously shown to represent major species AD patients. When compared Abeta(1-42), this peptide has stronger aggregation propensity...
Amyloid-β (Aβ) peptides, starting with pyroglutamate at the third residue (pyroGlu-3 Aβ), are a major species deposited in brain of Alzheimer disease (AD) patients. Recent studies suggest that this isoform shows higher toxicity and amyloidogenecity when compared to full-length Aβ peptides. Here, we report first comprehensive comparative IHC evaluation pyroGlu-3 deposition humans animal models. PyroGlu-3 immunoreactivity (IR) is abundant plaques cerebral amyloid angiopathy AD Down syndrome...
Brains of Alzheimer's disease (AD) patients are characterized in part by the formation high molecular weight aggregates amyloid-β (Aβ) peptides, which interfere with neuronal function and provoke cell death. The pyroglutamate (pGlu) modification Aβ was demonstrated to be catalyzed enzyme glutaminyl cyclase (QC) enhance pathogenicity neurotoxicity. Here, we addressed role QC AD pathogenesis human cortex. Two sets postmortem brain tissue from a total 13 non-demented controls 11 cases were...
Compelling evidence suggests that N-terminally truncated and pyroglutamyl-modified amyloid-β (Aβ) peptides play a major role in the development of Alzheimer's disease. Posttranslational formation pyroglutamic acid (pGlu) at position 3 or 11 Aβ implies cyclization an N-terminal glutamate residue rendering modified peptide degradation resistant, more hydrophobic, prone to aggregation. Previous studies using artificial substrates suggested potential involvement enzyme glutaminyl cyclase...
Posttranslational amyloid-β (Aβ) modification is considered to play an important role in Alzheimer's disease (AD) etiology. An N-terminally modified Aβ species, pyroglutamate-amyloid-β (pE3-Aβ), has been described as a major constituent of deposits specific human AD but absent normal aging. Formed via cyclization truncated species by glutaminyl cyclase (QC; QPCT) and/or its isoenzyme (isoQC; QPCTL), pE3-Aβ aggregates rapidly and known seed additional aggregation. To directly investigate...
Research Article20 July 2011Open Access The isoenzyme of glutaminyl cyclase is an important regulator monocyte infiltration under inflammatory conditions Holger Cynis Probiodrug AG, Halle, Germany Search for more papers by this author Torsten Hoffmann Daniel Friedrich Astrid Kehlen Kathrin Gans Martin Kleinschmidt Jens-Ulrich Rahfeld Raik Wolf Michael Wermann Anett Stephan Monique Haegele Reinhard Sedlmeier Ingenium Pharmaceuticals GmbH, Martinsried, Sigrid Graubner Wolfgang Jagla Anke...
Pyroglutamate (pGlu)-modified amyloid peptides have been identified in sporadic and familial forms of Alzheimer's disease (AD) the inherited disorders British Danish Dementia (FBD FDD). In this study, we characterized aggregation amyloid-β protein Aβ37, Aβ38, Aβ40, Aβ42 ADan species vitro, which were modified by N-terminal pGlu (pGlu-Aβ3-x, pGlu-ADan) or possess intact N-terminus (Aβ1-x, ADan). The pGlu-modification confers rapid formation oligomers short fibrillar aggregates. accordance...
Abstract Modified amyloid β (Aβ) peptides represent major constituents of the deposits in Alzheimer’s disease and Down’s syndrome. In particular, N‐terminal pyroglutamate (pGlu) following truncation renders Aβ more stable, increases hydrophobicity aggregation velocity. Recent evidence based on vitro studies suggests that cyclization glutamic acid, leading to pGlu‐Aβ, is catalyzed by enzyme glutaminyl cyclase (QC) limited proteolysis at N‐terminus. Here, we studied pGlu‐formation rat QC as...
In the hippocampal formation of Alzheimer's disease (AD) patients, both focal and diffuse deposits Aβ peptides appear in a subregion- layer-specific manner. Recently, pyroglutamate (pGlu or pE)-modified were identified as highly pathogenic seeding peptide species. Since pE modification is catalyzed by glutaminyl cyclase (QC) this enzyme emerged novel pharmacological target for AD therapy. Here, we reveal role QC different types pE-Aβ aggregates. First, demonstrate that both, are present...
The brains of Alzheimer's disease (AD) patients are characterized by deposits Abeta peptides and accompanying chronic inflammation. Here, we provide evidence that the enzyme isoglutaminyl cyclase (isoQC) is a novel factor contributing to both aspects AD pathology. Two putative substrates isoQC, N-truncated monocyte chemoattractant chemokine CCL2, undergo isoQC-catalyzed pyroglutamate (pGlu) modification. This triggers aggregation facilitates biological activity which collectively results in...
Abstract Background Hyperphosphorylation and intraneuronal aggregation of the microtubule-associated protein tau is a major pathological hallmark Alzheimer’s disease (AD) brain. Of special interest effect cerebral amyloid beta deposition, second main AD, on human pathology. Therefore, studying influence amyloidosis in novel knock-in (htau-KI) mouse model could help to reveal new details their interplay. Methods We studied effects htau-KI under fast-progressing 5xFAD mice terms correlation...
Glutaminyl cyclases (QCs) catalyze the formation of pyroglutamate residues at N-terminus several peptides and proteins from plants animals. Recently, isoenzymes mammalian QCs have been identified. In order to gain further insight into biochemical characteristics isoQCs, human murine enzymes were expressed in secretory pathway Pichia pastoris. Replacement N-terminal signal anchor by an alpha-factor prepropeptide Saccharomyces cerevisiae resulted poor secretion protein. Insertion glycosylation...
Abstract The hepatic content of amyloid beta (Aβ) decreases drastically in human and rodent cirrhosis highlighting the importance understanding consequences Aβ deficiency liver. This is especially relevant view recent advances anti‐Aβ therapies for Alzheimer's disease (AD). Here, it shown that partial loss transgenic AD mice immunized with antibody 3D6 its absence precursor protein (APP) knockout (APP‐KO), as well liver spheroids APP knockdown upregulates classical hallmarks fibrosis, smooth...
Glutaminyl cyclases (QCs) catalyze the formation of pyroglutamate (pGlu) residues at N terminus peptides and proteins. Hypothalamic pGlu hormones, such as thyrotropin-releasing hormone gonadotropin-releasing are essential for regulation metabolism fertility in hypothalamic pituitary thyroid gonadal axes, respectively. Here, we analyzed consequences constitutive genetic QC ablation on endocrine functions behavior adult mice. Adult homozygous knock-out mice fertile behave indistinguishably...
Summary Inflammation is an integral part of non‐alcoholic fatty liver disease (NAFLD), the most prevalent form hepatic pathology found in general population. In this context, recently we have examined potential role Glutaminyl Cyclases ( QC and iso ), their inhibitors, maturation chemokines, for example, monocyte chemoattractant protein 1 MCP ‐1, CCL 2), to generate bioactive conformation. Catalysis by leads formation N‐terminal pyroglutamate residue protecting 2 against degradation...
CX3CL1 (fractalkine) is a unique member of the CX3C chemokine family and mediates both adhesion cell migration in inflammatory processes. Frequently, activity chemokines depends on modified N-terminus as described for CCL2 to pGlu- (pyroglutamate) residue by QC (glutaminyl cyclase) activity. Here, we assess role pGlu-modified domain human endothelial smooth muscle cells. For first time, demonstrated using MS that (QPCT, gene name QC) or its isoenzyme isoQC (iso-glutaminyl (QPCTL, isoQC)...
Posttranslational modifications of beta amyloid (Aβ) have been shown to affect its biophysical and neurophysiological properties. One these is N-terminal pyroglutamate (pE) formation. Enzymatic glutaminyl cyclase (QC) activity catalyzes cyclization truncated Aβ(3-x), generating pE3-Aβ. Compared unmodified Aβ, pE3-Aβ more hydrophobic neurotoxic. In addition, it accelerates aggregation other Aβ species. To directly investigate formation toxicity in vivo, transgenic (tg) ETNA (E at the...