Dose-dependent folic acid and memantine treatments promote synergistic or additive protection against Aβ(25-35) peptide-induced apoptosis in SH-SY5Y cells mediated by mitochondria stress-associated death signals

Increased dietary folic acid (FA) is associated with reduced risks of Alzheimer's disease (AD). The AD drug memantine (Mn) has had limited therapeutic effects for the treatment of patients with moderate to severe AD. This study investigated whether and the underlying mechanisms by which the combination of Mn and FA may have synergistic or additive effects in protecting against amyloid-beta((25-35)) peptide (A beta)-induced neurocytotoxicity. A beta treatment of human neuroblastoma SH-SY5Y cells significantly induced a 6-fold increase of apoptotic cells compared with the A beta-untreated group. Preincubation of A beta-exposed cells with FA (500 mu M) or.Mn (20 mu M) caused a 22% and 10% reduction of apoptotic cells, respectively, whereas the combo-treatments at such doses synergistically alleviated A beta-induced apoptosis by 60% (P < 0.05). The apoptotic protection by the combo-treatments coincided with attenuating A beta-elicited mitochondrial (mt) membrane depolarization and abolishing A beta-induced mt cytochrome c release to the cytosol. Increased levels of FA at 1000 mu M,4 in combination with 20 mu M Mn exerted an additive protection against A beta((25-35))-induced-apoptosis as compared to the isolate Mn group (P < 0.05). The combo-treatments reversed A beta-elicited mt membrane depolarization, attenuated A beta-elicited mt cytochrome c release to the cytosol, and diminished A beta-promoted superoxide generation. The apoptotic-protection by such combo-treatments was partially abolished by carbonyl cyanide 3-chlorophenylhydrazone (mt membrane potential uncoupler) and sodium azide (mt cytochrome c oxidase inhibitor). Taken together, the data demonstrated that dose-dependent FA and Mn synergistically or additively protected SH-SY5Y cells against A beta-induced apoptosis, which was partially, if not completely, mediated by mt stress-associated death signals. (C) 2013 Elsevier Ltd. All rights reserved.