Multiple mechanisms of dimethyl fumarate in amyloid β-induced neurotoxicity in human neuronal cells

Alzheimer disease (AD) is characterized by a complex heterogeneity of pathological changes, and any therapeutic approach categoricallyrequires a multi-targeted way. It has been demonstrated that together with the hallmarks of the disease such as neurofibrillary tangles andsenile plaques, oxidative and inflammatory stress covered an important role. Dimethyl fumarate (DMF) is an orally bioavailable methyl ester offumaric acid and activator of Nrf2 with potential neuroprotective and immunomodulating activities. Therefore, the aim of the present work wasto evaluate the potential beneficial effects of DMF, compared with its active metabolite monomethyl fumarate (MMF) (both at 30 μM) in anin vitro Alzheimer’s model using SH-SY5Y human neuroblastoma cell lines stimulated with amyloid-beta (Aβ). Moreover, the effect of DMF,compared with MMF, was evaluate by an ex vivo model using organotypic hippocampal slice cultures stimulated with Aβ1-42 (1 lg/ml), to betterunderstand its action in a pathological setting. In both models, DMF pre-treatment (30 μM) preserved cellular viability from Ab stimulation,reducing tau hyper-phosphorylation, much more efficiently then MMF (30 μM). Moreover, DMF was able to induce an activation of manganesesuperoxide dismutase (MnSOD) and heme-oxygenase-1 (HO-1), decreasing the severity of oxidative stress. Our results showed important multi-protective effects of DMF pre-treatment from Aβ stimulation both in in vitro and ex vivo models, highlighting an Nrf2/NF-κB-dependent mechanism,which could provide a valuable support to the therapies for neurodegenerative diseases today.