A5079382118- Alzheimer's disease research and treatments
- Amino Acid Enzymes and Metabolism
- Computational Drug Discovery Methods
- Cholinesterase and Neurodegenerative Diseases
- Drug Transport and Resistance Mechanisms
- Supramolecular Self-Assembly in Materials
- Chemical Synthesis and Analysis
- Prion Diseases and Protein Misfolding
- Tryptophan and brain disorders
- Protein Structure and Dynamics
- Machine Learning in Bioinformatics
- Neuroinflammation and Neurodegeneration Mechanisms
- Dementia and Cognitive Impairment Research
- Neuroscience and Neuropharmacology Research
- Amyotrophic Lateral Sclerosis Research
- Parkinson's Disease Mechanisms and Treatments
- Biochemical effects in animals
- Ginkgo biloba and Cashew Applications
- S100 Proteins and Annexins
- Pain Mechanisms and Treatments
- Nuclear Receptors and Signaling
- Analytical Chemistry and Chromatography
- Protein Hydrolysis and Bioactive Peptides
- Click Chemistry and Applications
- Medicinal Plants and Neuroprotection
Forschungszentrum Jülich
2016-2025
Heinrich Heine University Düsseldorf
2010-2021
Institute for Complex Systems
2018
Stadtwerke Jülich (Germany)
2018
Mammalian prions refold host glycosylphosphatidylinositol-anchored PrPC into β-sheet–rich PrPSc. PrPSc is rapidly truncated a C-terminal PrP27-30 core that stable for days in endolysosomes. The nature of cell-associated prions, their attachment to membranes and rafts, subcellular locations are poorly understood; live prion visualization has not previously been achieved. A key obstacle the inaccessibility epitopes. We overcame this hurdle by focusing on nascent full-length rather than its...
Soluble amyloid beta (Aβ) oligomers have been suggested as initiating Aβ related neuropathologic change in Alzheimer's disease (AD) but their quantitative distribution and chronological sequence within the AD continuum remain unclear.
Abstract Introduction PRI‐002 is an orally available anti–amyloid beta (Aβ) prionic compound developed for direct disassembly of toxic Aβ oligomers relevant to Alzheimer's disease. Methods Two placebo‐controlled clinical phase I trials with oral dosing were conducted in healthy young subjects: A single ascending dose trial (4, 12, 36, 108, or 320 mg placebo) 40 participants followed by a multiple study daily 160 14 days 28 24 participants. The main objectives safety, tolerability, and...
Abstract While amyloid-β protein (Aβ) aggregation into insoluble plaques is one of the pathological hallmarks Alzheimer’s disease (AD), soluble oligomeric Aβ has been hypothesized to be responsible for synapse damage, neurodegeneration, learning, and memory deficits in AD. Here, we investigate vitro vivo efficacy d -enantiomeric peptide RD2, a rationally designed derivative previously described lead compound D3, which developed efficiently eliminate toxic Aβ42 oligomers as promising...
Strong evidence exists for a central role of amyloid β-protein (Aβ) oligomers in the pathogenesis Alzheimer's disease. We have developed fast, reliable and robust vitro assay, termed QIAD, to quantify effect any compound on Aβ aggregate size distribution. Applying we studied homotaurine, scyllo-inositol, EGCG, benzofuran derivative KMS88009, ZAβ3W, D-enantiomeric peptide D3 its tandem version D3D3 aggregation. The predictive power assay vivo efficacy is demonstrated by comparing oligomer...
Targeting toxic amyloid beta (Aβ) oligomers is currently a very attractive drug development strategy for treatment of Alzheimer´s disease. Using mirror-image phage display against Aβ1-42, we have previously identified the fully D-enantiomeric peptide D3, which able to eliminate Aβ and has proven therapeutic potential in transgenic disease animal models. However, there little information on pharmacokinetic behaviour peptides general. Therefore, conducted experiments with tritium labelled...
The elimination of amyloid beta (Aβ) oligomers is a promising strategy for therapeutic drug development Alzheimer's disease (AD). AD mouse models that develop Aβ pathology have been used to demonstrate in vivo efficacy compounds later failed clinical development. Here, we analyze the concentration and size distribution different transgenic human brain samples by surface-based fluorescence intensity analysis (sFIDA), highly sensitive method detecting quantitating protein aggregates. We dose-...
More than the sum of its parts: Novel hybrid compounds consisting an organic β-sheet-breaking moiety and a signaling, D-enantiomeric Aβ-recognizing peptide have been designed (see picture). The compounds, which were chemically synthesized characterized by several techniques, combine rational design drug selection from libraries inhibit Aβ oligomerization Aβ-induced synaptic pathology. Detailed facts importance to specialist readers are published as "Supporting Information". Such documents...
Oligomers of the amyloid-β (Aβ) protein are suspected to be responsible for development and progression Alzheimer's disease. Thus, compounds that able eliminate already formed toxic Aβ oligomers is very desirable. Here, we describe in vivo efficacy compound RD2, which was developed directly specifically oligomers. In a truly therapeutic, rather than preventive study, oral treatment with RD2 reverse cognitive deficits significantly reduce pathology old-aged transgenic Disease mice full-blown...
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that associated with the aggregation of amyloid β protein (Aβ). Aβ oligomers are currently thought to be major neurotoxic agent responsible for development and progression. Thus, their elimination highly desirable therapy development. Our therapeutic approach aims at specific direct toxic by stabilizing monomers in an aggregation-incompetent conformation. We have proven our lead compound “D3”, all d-enantiomeric-peptide,...
Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder leading to dementia. Aggregation of the amyloid-β peptide (Aβ) plays an important role in disease, with Aβ oligomers representing most toxic species. Previously, we have developed oligomer eliminating therapeutic compound RD2 consisting solely D-enantiomeric amino acid residues. has been described oral bioavailability more than 75% and improve cognition transgenic mouse models after administration. In present study, further...
Alzheimer's disease (AD) is a neurodegenerative disorder and the most common type of dementia. Until now, there no curative therapy available. Previously, we selected amyloid-beta (Aβ) targeting peptide D3 consisting 12 d-enantiomeric amino acid residues by mirror image phage display as potential drug candidate for treatment AD. In current approach, investigated optimization linear with free C-terminus (D3COOH) chemical modifications. First, impact net charge was second, cyclization...
Amyloid-beta (Aβ) oligomers are thought to be causative for the development and progression of Alzheimer's disease (AD). Starting from Aβ oligomer eliminating d-enantiomeric peptide D3, we developed applied a two-step procedure based on microarrays identify D3 derivatives with increased binding affinity specificity monomeric Aβ(1–42) further enhance elimination efficacy. Out more than 1000 derivatives, selected seven novel d-peptides, named ANK1 ANK7, characterized them in detail vitro. All...
The aggregation of amyloid-β (Aβ) is postulated to be the crucial event in Alzheimer's disease (AD). In particular, small neurotoxic Aβ oligomers are considered responsible for development and progression AD. Therefore, elimination thesis represents a potential causal therapy Starting from well-characterized d-enantiomeric peptide D3, we identified D3 derivatives that bind monomeric Aβ. underlying hypothesis ligands stabilize these species within various equilibria with assemblies, leading...
The aggregation of amyloid-β (Aβ) into oligomers and fibrillary structures is critical for the pathogenesis Alzheimer's disease (AD). Recently, research effort has been focused on developing novel agents that can preferentially suppress Aβ oligomer mediated toxicities, example, by directly targeting these toxic assemblies. compound RD2 developed optimized Aβ42 monomer binding stabilization in its native intrinsically disordered conformation. It demonstrated to improve even reverse cognitive...
Abstract Background Misfolding and aggregation of amyloid β (Aβ), along with neurofibrillary tangles consisting aggregated Tau species, are pathological hallmarks Alzheimer’s disease (AD) onset progression. In this study, we hypothesized the clearance Aβ aggregates from brain body into gut. Methods To investigate this, used surface-based fluorescence intensity distribution analysis (sFIDA) to determine aggregate concentrations in feces 26 AD patients 31 healthy controls (HC). Results were...
Alzheimer´s disease is the most prominent type of dementia and currently no causative treatment available. According to recent studies, oligomeric species amyloid beta (Aβ) peptide appear be toxic Aβ assemblies. monomers, however, may not per se even have a neuroprotective role. Here we describe competitive mirror image phage display procedure that allowed us identify preferentially Aβ1–42 monomer binding thereby stabilizing peptides, which destabilize eliminate oligomer species. One called...
Multiple sources of evidence suggest that soluble amyloid β (Aβ)-oligomers are responsible for the development and progression Alzheimer’s disease (AD). In order to specifically eliminate these toxic Aβ-oligomers, our group has developed a variety all-d-peptides over past years. One them, RD2, been intensively studied showed such convincing in vitro vivo properties it is currently clinical trials. further optimize compounds elucidate characteristics therapeutic d-peptides, several rational...
Alzheimer's disease, a multifactorial incurable disorder, is mainly characterised by progressive neurodegeneration, extracellular accumulation of amyloid-β protein (Aβ), and intracellular aggregation hyperphosphorylated tau protein. During the last years, Aβ oligomers have been claimed to be disease causing agent. Consequently, development compounds that are able disrupt already existing highly desirable. We developed d-enantiomeric peptides, consisting solely amino acid residues, for direct...