Anti-Parkinsonian agents have anti-amyloidogenic activity for Alzheimer's β-amyloid fibrils in vitro

Inhibition of the accumulation of amyloid β-peptide (Aβ) and the formation of β-amyloid fibrils (fAβ) from Aβ, as well as the destabilization of preformed fAβ in the central nervous system would be attractive therapeutic targets for the treatment of Alzheimer's disease (AD). Many studies have demonstrated that oxidative damage plays a central role in AD pathogenesis, as well as Parkinson disease (PD). Among the antioxidant strategies proposed, increasing evidence points to the possibility of achieving neuroprotection by dopamine agonists, as well as monoamine oxidase B (MAO-B) inhibitors. Actually, the beneficial effect of selegiline, a MAO-B inhibitor, in AD has been noted in several clinical studies. On the reverse, antimuscarinic agents have been reported to accelerate β-amyloidosis and senile plaque formation in PD. Using fluorescence spectroscopic analysis with thioflavin T and electron microscopic studies, we examined the effects of anti-Parkinsonian agents, dopamine, levodopa, pergolide, bromocriptine, selegiline, and trihexyphenidyl on the formation, extension, and destabilization of fAβ(1-40) and fAβ(1-42) at pH 7.5 at 37 °C in vitro. The anti-Parkinsonian agents other than trihexyphenidyl dose-dependently inhibited fAβ formation from Aβ(1-40) and Aβ(1-42), as well as their extension. Moreover, these agents dose-dependently destabilized preformed fAβs. The overall activity of the molecules examined was in the order of: dopamine > selegiline > levodopa = pergolide > bromocriptine. Although the exact mechanism of the anti-amyloidogenic activity of these agents is unclear, these and other structurally related compounds could be key molecules for the development of therapeutics for AD and other conformational diseases.