Resveratrol Attenuates Formaldehyde Induced Hyperphosphorylation of Tau Protein and Cytotoxicity in N2a Cells

Abstract

Recent studies have demonstrated that formaldehyde (FA)—induced neurotoxicity is important in the pathogenesis of Alzheimer's disease (AD). Elevated levels of FA have been associated with memory impairments and the main hallmarks of AD pathology, including β-amyloid plaques, tau protein hyperphosphorylation, and neuronal loss. Resveratrol (Res), as a polyphenol anti-oxidant, has been considered to have therapeutic potential for the treatment of AD. However, it has not been elucidated whether Res can exert its neuroprotective effects against FA-induced neuronal damages related to AD pathology. To answer this question, the effects of Res were investigated on Neuro-2a (N2a) cells prior to and after FA exposure. The experiments found that pre-treatment with Res significantly decreased FA-induced cytotoxicity, reduced cell apoptosis rates, and inhibited the hyperphosphorylation of tau protein at Thr181 in a dose-dependent manner. Further tests revealed that this effect was associated with the suppression of glycogen synthase kinase (GSK-3β) and calmodulin-dependent protein kinase II (CaMKII) activities, both of which are important kinases for tau protein hyperphosphorylation. In addition, Res was found to increase the activity of phosphoseryl/phosphothreonyl protein phosphatase-2A (PP2A). In summary, these findings provide evidence that Res protects N2a cells from FA-induced damages and suggests that inhibition of GSK-3β and CaMKII and the activation of PP2A by Res protect against the hyperphosphorylation and/or mediates the dephosphorylation of tau protein, respectively. These possible mechanisms underlying the neuroprotective effects of Res against FA-induced damages provide another perspective on AD treatment via inhibition of tau protein hyperhosphorylation.

PAMAM dendrimers as a carbamazepine delivery system for neurodegenerative diseases: A biophysical and nanotoxicological characterization

“…To study the influence of the proposed delivery systems on cell culture and analyze possible cytotoxic effects, we used the N2a cell line, a fast-growing mouse neuroblastoma cell line that has been widely used to study neuronal differentiation, neurite growth, synaptogenesis and signaling pathway. Also, N2a cells have been used to study neurotoxicity, Alzheimer's disease and asymmetric division of mammalian cell lines (He et al, 2017;Yang et al, 2014). Cytotoxicity upon treatment with CBZ, D or D-CBZ was measured by colorimetric methods as crystal violet (CV) staining, MTT assay, and neutral red (NR) uptake.…”

Recent developments in solid lipid nanoparticle and surface-modified solid lipid nanoparticle delivery systems for oral delivery of phyto-bioactive compounds in various chronic diseases

“…Recently, resveratrol has gained more interest to treat AD due to its greater neuroprotective effect, and many studies confirmed that resveratrol treatment significantly improved the cognition and biochemical parameters. [114][115][116][117][118][119][120][121][122][123] Recently, resveratrol-loaded SLN was studied for its bioavailability and brain delivery. Resveratrol was efficiently delivered to the brain and exhibited its potential bioactivity.…”

Involvement of calpain in the neuropathogenesis of Alzheimer’s disease

“…In support, a correlation with cognitive dysfunction in MCI and AD subjects was found with the reduction of T286‐autophosphorylation in apical dendrites of granule cells of the DG . Resveratrol was shown to decrease τ hyperphosphorylation via suppression of GSK3β and CaMKII activities in N2A cells exposed to formaldehyde . Strong and sustained stress‐like acute severe CO poisoning could lead to both calpain and CaMKII expression and activation .…”