The role of protein aggregate maturation in Alzheimer's disease and other neurodegenerative disorders and its potential for disease monitoring and differential diagnosis.

This project aims at identifying changes in the composition of Alzheimer’s disease (AD)-related protein aggregates throughout preclinical and clinical stages of the disease. Moreover, we want to find out whether such “maturation changes” can be clinically detected by specific biomarkers or may represent potential therapeutic targets. To address these aims we analyze human brain tissue samples from non-AD, preclinical AD, and symptomatic AD cases pathologically and biochemically. Thus, we will employ immunoprecipitation techniques and mass spectrometry to identify novel proteins bound to AD-related protein aggregates, i.e. amyloid aggregates and tau-protein containing neurofibrillary tangles. Moreover, PET-tracer candidates will be tested in vitro for their binding properties to such aggregates in different stages of the AD pathogenesis. Thereby, we will find out which pathologies and what stages of the respective pathologies can be detected with these biomarkers. To test the disease propagating potential of protein aggregates at different stages of the disease we will isolate them from respective human brain samples and inject them into the brains of transgenic mouse models for AD-related pathologies. With the results from these experiments we will know which steps in the disease progression of AD are suited for therapeutic interaction and which potential target proteins exist to interact with.