Signatures of modified Abeta peptides in brains of Alzheimer’s disease subjects revealed by novel monoclonal antibodies
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
In this proposal we tested the hypothesis that defined Abeta (Aβ) peptide variants contribute to the pathogenesis and progression of Alzheimer’s disease (AD) and other types of dementia in a specific manner. Deposits of Aβ peptides in amyloid plaques are a histopathological hallmark of AD. Aβ 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 Aβ peptide variants to the initiation and progression of AD and other types of dementia are not fully established. Therefore, we employed already existing and novel monoclonal antibodies generated by us for the comparative analyses of phosphorylated, nitrated, pyroglutamate- and isoaspartate-modified Aβ peptides in brain parenchyma and cerebral blood vessels by immunohistochemical and biochemical methods. We analysed 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 revealed aggregation characteristics of modified Aβ peptides. In summary, this study should reveal whether these modified forms of Aβ might represent potent drivers in different types of dementia. We identified the isoAsp7-Aβ variant in both analytical methods as the most abundant Aβ form in all clinical conditions, followed by Aβ4-X, pGlu3-Aβ, pGlu11-Aβ and pSer8-Aβ. There was a strong positive correlation between isoAsp7-Aβ and Thal phase and a negative correlation between isoAsp7-Aβ and performance in mini mental state examination at six months before death. Furthermore, we unrevealed an association between the isoAsp7-Aβ variant and the APOE alleles. We conclude that targeting Aβ posttranslational modifications, and in particular the abundant isoAsp7-Aβ variant, might be considered for diagnostic and therapeutic approaches in different types of dementia. In addition, we quantified these post-translationally modified Aβ species in brain of transgenic 5xFAD mice during aging and compared the data to human brain samples of AD patients. Finally, we run a comparative treatment study in 5xFAD mice with antibodies directed against three different Aβ variants.
Publications
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Identification of isoAsp7-Aβ as a major Aβ variant in Alzheimer’s disease, dementia with Lewy bodies and vascular dementia. Acta Neuropathologica, 148(1).
Schrempel, Sarah; Kottwitz, Anna Katharina; Piechotta, Anke; Gnoth, Kathrin; Büschgens, Luca; Hartlage-Rübsamen, Maike; Morawski, Markus; Schenk, Mathias; Kleinschmidt, Martin; Serrano, Geidy E.; Beach, Thomas G.; Rostagno, Agueda; Ghiso, Jorge; Heneka, Michael T.; Walter, Jochen; Wirths, Oliver; Schilling, Stephan & Roßner, Steffen
