Dimethyl fumarate exerts neuroprotection by modulating calcineurin/NFAT1 and NFκB dependent BACE1 activity in Aβ1-42 treated neuroblastoma SH-SY5Y cells

Abstract

Ample studies indicate that calcineurin, a Ca2+/calmodulin-sensitive phosphatase, plays a key role in the initiation and/or clinical progression of Alzheimer's disease, and alteration of calcineurin has been confirmed in Alzheimer’s disease brain, impacting tau proteins and amyloid beta (Aβ) levels and resulting in neuronal cell death. As, it is sensible to deliberate the likelihood of calcineurin inhibition as a pharmacological target in the progress of novel Alzheimer’s disease therapies, we investigated the neuroprotective efficacy of dimethyl fumarate (DMF) via calcineurin dependent downstream targets in oligomeric Aβ1-42 treated neuroblastoma SH-SY5Y cells. DMF pre-treatment reduced LDH release, increased cell survival and decreased calcineurin activity in Aβ1-42-incubated cells. DMF was found to block calcineurin dependent apoptosis induced by Aβ1-42 through Bcl-2 linked death protein (BAD) and cAMP response element binding (CREB) dephosphorylation; moreover, rescued the opposing effect of Aβ1-42 on CREB-driven transcription in cells transfected with the CRE-SEAP reporter gene indicating its efficacy on long term potentiation and synaptic plasticity. DMF reversed Aβ1-42-induced enhancement in the active form of nuclear factor of activated T-cells (NFAT1) and further associated beta-site amyloid precursor protein cleaving enzyme-1 (BACE1) expression, BACE1 promoter activity and BACE1 enzymatic activity. DMF exhibited another neuroprotective mechanism against Aβ1-42 treatment by reducing nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB) dependent BACE1 gene transcription. DMF does not alter either beta amyloid precursor protein (βAPP) or its mRNA levels in SH-SY5Y cells, confirming that it does not possess amyloidogenic effect. Inhibiting molecular events related to Aβ1-42-induced calcineurin activity by DMF, may be an approach towards finding suitable treatment for Alzheimer’s disease.