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Abstract: Amyloid beta (1–42) peptide is considered responsible for the formation of senile plaques that accumulate in the brains of patients with Alzheimer''s disease (AD). In the last years considerable attention has been focused on identifying natural food products, such as phytochemicals that prevent or almost retard the appearance of amyloid beta (1–42)-related neurotoxic effects. In this study, human neuroblastoma cells (IMR-32) was used as system model to evaluate the protective role of rhaponticin (3,3′,5-trihydroxy-4′-methoxystilbene 3-O-d-glucoside) a stilbene glucoside extracted from rhubarb roots (Rhei rhizoma) and rhapontigenin, its aglycone metabolite, against amyloid beta (1–42)-dependent toxicity. The obtained results show that rhapontigenin maintains significant cell viability in a dose-dependent manner and it exerts a protective effect on mitochondrial functionality, as evidenced by mitochondrial oxygen consumption experiments. A similar behaviour, but to a lesser extent, has been shown by rhaponticin. The protective mechanism mediated by the two stilbenes could be related to their effect on bcl-2 gene family expression. Bax, a pro-apoptotic gene, resulted down-regulated by the treatment with rhaponticin and rhapontigenin compared with the results obtained in the presence of amyloid beta (1–42) peptide. Conversely, bcl-2, an anti-apoptotic gene, highly down-regulated by amyloid beta (1–42) treatment, resulted expressed in the presence of stilbenes similarly to that shown by control cells. The obtained results support the hypothesis that amyloid beta (1–42)-induced neurotoxicity occurs via bax over-expression, bcl-2 down-regulation, firstly indicating that rhaponticin and its aglycone moiety may alter this cell death pathway. Based on these studies, we suggest that rhaponticin and its main metabolite could be developed as agents for the management of AD. [Copyright &y& Elsevier]

Abstract: The β amyloid (Aβ), the major protein component of brain senile plaques in Alzheimer’s disease, is known to be directly responsible for the production of free radicals toxic to brain tissue and the redox state of Met-35 residue seems to play a particular and critical role in peptide’s neurotoxic actions. In this study, we investigated, in human neuroblastoma cells (IMR-32), the relationship between the oxidative state of methionine, and both neurotoxic and pro-apoptotic actions induced by Aβ-peptide, comparing the effects of native peptide, in which the Met-35 is present in the reduced state, with those of a modified peptide with oxidized Met-35 (Aβ(1–42)35Met-ox), as well as an Aβ-derivative with Met-35 substituted with norleucine (Aβ(1–42)35Nle). The obtained results show that Aβ induces a time-dependent decrease in cell viability; Aβ(1–42)35Met-ox was significantly less potent, though inducing a remarkable decrease in cell viability compared to control. On the contrary, no toxic effects were observed after treatment with Aβ(1–42)35Nle. Aβ-peptide as well as the amyloid modified peptide with oxidized Met-35 induced the pro-apoptotic gene bax over-expression after 24 h, whereas Aβ(1–42)35Nle had no effect. Conversely, bcl-2, an anti-apoptotic gene, became highly down-regulated by Aβ peptide treatment, in contrast to that evidenced by the Aβ(1–42)35Met-ox peptide. Finally, Aβ caused an increase in caspase-3 activity to be higher with respect to that shown by Aβ(1–42)35Met-ox while Aβ(1–42)35Nle had no effect. These results support the hypothesis that Aβ-induced neurotoxicity occurs via bax over-expression, bcl-2 down-regulation, and caspase-3 activation, first indicating that methionine 35 redox state may alter this cell death pathway. [Copyright &y& Elsevier]