Structure and propagation of beta-amyloid aggregates

• Applicant: Professor Dr. Marcus Fändrich
• Subject Area: Biochemistry
• Term: from 2012 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 214743469

The deposition of β-amyloid (Aβ) peptide as amyloid fibrils is a hallmark of neurodegenerative conditions, such as cerebral amyloid angiopathy and Alzheimer’s disease. Underlying these events is a molecular self-assembly reaction that can be seeded in vitro by preformed amyloid fibrils and in vivo by intracerebral injection of Aβ-containing brain extracts into Alzheimer mouse models. While the in vivo seeding activity of brain extracts was shown to critically depend on Aβ peptide, the further determinants of amyloid propagation have remained enigmatic. In vitro preparations of Aβ peptide did not efficiently induce Aβ amyloidosis in mice, suggesting the involvement of a specific conformation of Aβ peptide or a currently unknown molecular cofactor. To address these issues and to resolve the molecular conformations of different Aβ aggregates, we will employ a battery of biophysical and biological techniques, ranging from structural biology and analytical chemistry to animal studies. The expected results aim for new insights into the conformational basis of amyloidotic protein misfolding diseases, and they will be relevant for understanding related biological phenomena from the spreading of amyloid aggregates to the development of molecular strains.

• DFG Programme: Research Grants