Aromatic interactions among beta-amyloid peptides and small polycyclic molecules: possible mechanisms of fibrillogenesis inhibition

Different neurodegenerative disorders, like Huntington's, Alzheimer's, and spongiform encephalopathy diseases, have in common the presence of insoluble protein aggregates, generally termed "amyloid", that share several physicochemical features: a fibrillar morphology, a predominantly beta-sheet secondary structure, birefringence upon staining with the dye Congo red, insolubility in common solvents and detergents, and proteaseresistance. In the case of Alzheimer's disease (AD), in particular, senile extracellular deposits of beta-amyloid peptide (Abeta) fibrils (plaques) are observed. The conventional view has been that it is the amyloid aggregate that is pathological, but more recently an alternative view is emerging: the neurotoxic species would not be the insoluble aggregate itself, but rather soluble oligomeric species, including small globular structures, 2.7 to 6.0 nm in diameter, and curvilinear structures called "protofibrils". Conformational constrains and stacking interactions can play a key role in the fibrillogenesis process and protein-protein and peptide-peptide interactions -resulting in self-assembly phenomena of Abeta peptides yielding fibrils - can be modulated and influenced by small organic molecules. Polycyclic aromatic molecules are of special interest as they can disrupt the molecular architectures precursors of fibrils by means of aromatic interactions, like stacking interactions with tyrosine and phenylalanine residues of the beta-amyloid peptides.