Main neuropathological hallmarks of
Alzheimer's disease (AD) and other
neurodegenerative disorders are the deposition of neurofibrillary tangles consisting of abnormally phosphorylated
protein tau and of
senile plaques largely containing insoluble
beta-amyloid peptides (A beta), containing up to 43
amino acid residues derived from the
beta-amyloid precursor
protein. Such A beta-sheets become visible by using suitable histochemical methods. Molecular simulation showed that the central, alpha-helical, lipophilic, antigenic folding domain of the A beta-
peptide loop is a promising molecular target of beta-sheet breakers that thus prevent the polymerization of A beta into aggregates. It seems that di- and tetramers of A beta-
peptides have a beta-barrel- like structure. In the present review, an optimized neural network analysis was applied to recognize possible structure-activity relationships of
peptidomimetic beta-sheet breakers. The anti-aggregatory potency of beta-sheet breakers largely depends upon their total, electrostatic, and hydration energy as derived from their geometry-optimized conformations using the hybrid Gasteiger-molecular mechanics approach. Moreover, we also summarize
peptide misfolding in several disorders with distinct clinical symptoms, including
prion diseases and a broad variety of systemic
amyloidoses, as the common pathogenic step driving these disorders. In particular, conversion of nontoxic alpha-helix/random-coils to beta-sheet conformation was recognized as being critical in producing highly pathogenic
peptide assemblies. Whereas conventional
pharmacotherapy of AD is mainly focused on restoring
cholinergic activity and diminishing inflammatory responses as a consequence of
amyloid accumulation, we here survey potential approaches aimed at preventing or reserving the transition of neurotoxic
peptide species from alpha-helical/random coil to beta-sheet conformation and thus abrogating their effects in a broad variety of disorders.