Polypeptide and Protein Aggregates with Neurotoxic Properties in Neurodegenerative Disorders: Emphasis on β-Amyloid-Induced Dysfunction of Receptor-Mediated Signal Transduction Pathways

Polypeptides and proteins may undergo misfolding processes resulting in aggregates: oligomers and fibrils possessing toxic properties. In most cases a beta-structure will be formed with high tendency to form suprachemical structures, assemblies. The aggregation grade might play crucial role in the biological activities of protein assemblies. Protein aggregates bind to receptors or receptor complexes of neuronal and glial cells and activate signal transduction pathways. Beta amyloid may interact with Wnt receptors as well as increases the intracellular Ca-ion level in neurons. GSK-3beta activation causes tau-hyperphosphorylation and collaps of the microtubular system. β-amyloid triggers also a CD36 dependent signaling cascade and activates microglia. Other misfolded protein assemblies of alpha-synuclein, huntingtin and prion proteins similarly interact with receptor complexes and disturb signal transduction. Rational drug design may start after understanding these signalisation disturbances. Novel drugs will prevent receptor interaction with misfolded protein aggregates.