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

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In this proposal we would like to 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 not amyloid plaques, but their oligomeric and fibrillary precursors compromise neuronal function and are neurotoxic. 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 would like to 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 analyze 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 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 might represent potent drivers of disease progression due to their spatial and temporal expression patterns in brain and neurotoxicity.