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.