Three-dimensional structure of the lithostathine protofibril, a protein involved in Alzheimer's disease

Neurodegenerative diseases are characterized by the presence of filamentous aggregates of proteins. We previously established that lithostathine is a protein overexpressed in the pre-clinical stages of Alzheimer's disease. Fu rthermore, it is present in the pathognomonic lesions associated with Alzhe imer's disease, After self-proteolysis, the N-terminally truncated form of lithostathine leads to the formation of fibrillar aggregates. Here we obser ved using atomic force microscopy that these aggregates consisted of a netw ork of protofibrils, each of which had a twisted appearance. Electron micro scopy and image analysis showed that this twisted protofibril has a quadrup le helical structure. Three-dimensional X-ray structural data and the resul ts of biochemical experiments showed that when forming a protofibril, litho stathine was first assembled via lateral hydrophobic interactions into a te tramer, Each tetramer then linked up with another tetramer as the result of longitudinal electrostatic interactions. All these results were used to bu ild a structural model for the lithostathine protofibril called the quadrup le-helical filament (QHF-litho). In conclusion, lithostathine strongly rese mbles the prion protein in its dramatic proteolysis and amyloid proteins in its ability to form fibrils.