Group Prof. Dr. Steffen Roßner

Signatures of modified Abeta peptides in brains of Alzheimer's disease subjects revealed by novel monoclonal antibodies​​

In this project we will test the hypothesis that defined Abeta peptide variants contribute to the pathogenesis and progression of Alzheimer’s disease (AD) in a specific manner. Deposits of Abeta peptides in amyloid plaques are a histopathological hallmark of AD.

However, it is generally accepted that oligomeric and fibrillary precursors of amyloid plaques are the components which compromise neuronal function and cause neurotoxicity, and not the plaques themselves. Abeta peptides represent a heterogeneous group of peptides with differing biophysical and cell biological characteristics that are diversified by N-terminal truncation and other specific post-translational modifications. However, the contributions of defined Abeta peptide variants to the initiation and progression of AD are not fully established. Therefore, we will employ already existing and novel monoclonal antibodies generated by us for the comparative analyses of phosphorylated, nitrated, pyroglutamate- and isoaspartate-modified Abeta peptides in brain parenchyma and vessels by immunohistochemical and biochemical methods. We will analyse post mortem human brain tissue from pre-symptomatic and symptomatic AD cases in comparison to brain tissue from control subjects and subjects who suffered from vascular dementia and from dementia with Lewy bodies. Additionally, we will analyse brain tissue of AD mouse models and reveal aggregation characteristics and neurotoxic profiles of modified Abeta peptides in primary neuronal cell cultures. In summary, the results should reveal whether these modified forms of Abeta represent potent drivers of disease progression due to their spatial and temporal expression patterns in brain and neurotoxicity.    

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Enzymatic regulation of CCL2 bioactivity in neuroinflammation​

The present proposal focuses on the regulation of neuroinflammatory effects mediated by the C-C motif chemokine CCL2. We hypothesize that the biological activity of CCL2 for microglia/macrophage recruitment is tuned by enzyme-catalyzed post-translational modification.

On the one hand, N-terminal CCL2 truncation by dipeptidyl peptidase IV/CD26 (DP4) initiates further proteolytical degradation and abolishes its biological activity. On the other hand, N-terminal pyroglutamate modification catalyzed by the glutaminyl cyclases QC and/or isoQC protects CCL2 from proteolytical degradation and increases its biological activity. Thus, we consider the tandem of the QC/isoQC and DP4 enzymes as pro- and anti-inflammatory molecular check-points in neuroinflammation, as they may specifically modulate CCL2 activity and the functional outcome in neuroinflammatory conditions in vitro and in vivo.

Therefore we will analyze the temporal expression of QC, isoQC, DP4 and distinct CCL2 variants after ischemi​a in primary neural cells deficient in QC, isoQC, DP4 and CCL2 in vitro. We will also exemplify these regulated enzymatic actions in mouse brain using an inflammatory ischemia model and analyze microglia/macrophage recruitment to ischemic brain tissue. To address this issue, we will use knock-out mice deficient in QC, isoQC, DP4 and CCL2 and also monitor infarct volume and functional motor deficits. Thus, the proposal targets an important aspect related to the endogenous resolution of inflammation by enzyme processing pathways, which might be associated with a number of brain diseases. Furthermore, the results may provide implications for the use of clinically relevant enzyme inhibitors in neuroinflammatory conditions.​

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Contributions of glutaminyl cyclases to the pathogenesis of neurodegenerative disorders​

This proposal is based on the hypothesis that a number of brain disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD) share common pathogenic mechanisms leading to neurodegeneration.

A traditional view on these devastating disorders focuses on individual, disease-specific enzymes and/or aggregating proteins contributing to aspects of neuropathology. When they accumulate, synaptic function and neuronal survival are compromised. We believe that glutaminyl cyclase (QC)-modified peptides contribute to a higher aggregation tendency in these disease conditions. This has already been shown for seeding of Abeta plaques by pGlu-Abeta in Alzheimer's disease. We now strive to reveal basic mechanisms of pathogenic protein deposition that are shared in different clinical conditions and to develop novel therapeutic strategies for treatment of neurodegenerative disorders. A number of different cell culture and animal models will be used in order to mimic aspects of neurodegeneration induced by pathogenic protein aggregation.

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Are alpha-Synuclein fragments new substrates of glutaminyl cyclase?​

The enzymatic activity of glutaminyl cyclase (QC) is required for the generation of highly neurotoxic variants of Abeta peptides in brains of Alzheimer’s disease patients. These pGlu-Abeta peptides resist proteolytical degradation, display a high aggregation velocity and co-aggregate unmodified Abeta peptides.

The research project is based on our discovery that QC is also expressed by substantia nigra dopaminergic neurons in mice and human subjects and that a defined a-synuclein fragment is pGlu-modified by QC. Therefore, we will address the following research questions: (i) Are the concentration and/or enzymatic activity of QC increased in Parkinson's disease brain tissue? (ii) Are a-synuclein fragments substrates of QC? (iii) What are the aggregation characteristics of pGlu-modified a-synuclein peptides? (iv) Are these peptides present in substantia nigra of Parkinson's disease patients? Answering these questions should help to reveal novel pathological mechanisms of Parkinson‘s disease and to identify yet unknown factors contributing to degeneration of dopaminergic substantia nigra neurons.​

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