(Patho)physiological consequences of interactions of amyloid-β with cellular and non-cellular proteins; the role of “The Crossbeta Pathway”.

Abstract

Misfolding is an inherent and potentially problematic property of proteins. Misfolded proteins tend to aggregate and the deposition of aggregated proteins, termed amyloid, is associated with a variety of highly debilitating diseases known as amyloidoses, which includes Alzheimer's disease. In Alzheimer's disease amyloid-ß is considered to contribute to disease pathology. However, how amyloid-ß is normally cleared on the one hand, and how amyloid-ß induces cellular toxicity on the other end remains still unclear. First, several misfolded proteins with amyloid properties, including amyloid-ß, were tested in vitro for their ability to activate tPA-mediated plasminogen activation and FXII-mediated prekallikrein activation. Second, known FXII-activation surfaces were tested for their ability to form amyloid-like properties. Third, plasma of amyloidosis patients were analyzed for the presence of products of tPA and FXII activation. Fourth, the role of plasminogen activation on the effect of amyloid-ß on neurons was studied. A unique characteristic of misfolding in protein aggregation is the formation of crossbeta structure. In recent years we have identified proteins, including two homologous proteases, factor XII (FXII) and tissue-type plasminogen activator (tPA) that specifically recognize misfolded proteins, including amyloid-ß. Factor XII was known as initiator of the contact system, an enzymatic cascade in blood that was known to become activated when blood contacts ‘surface’ materials, but its physiological activator remained elusive. We found that FXII is activated by misfolded proteins with crossbeta structure and that this specifically leads to the formation of kallikrein in vitro and in patients with systemic amyloidosis. These results identified misfolded proteins as activators of FXII and have solved the paradoxical role of FXII in coagulation. Besides FXII we have demonstrated that tPA is activated by misfolded proteins with crossbeta structure in general. We also identified amyloid-binding cellular receptors. Our discoveries have uncovered new roles for the fibrinolytic system (tPA), the contact activation system (FXII) and cellular receptors, which open avenues for the development of novel disease modifying agents.