Syringic acid demonstrates promising protective effect against tau fibrillization and cytotoxicity through regulation of endoplasmic reticulum stress-mediated pathway as a prelude to Alzheimer's disease

There are several studies reporting that different plant-based metabolites are potential inhibitors of protein amyloid fibrillation. As chemical features of metabolites can regulate protein aggregation process, in the present in vitro investigation, tau protein was selected as a model of Alzheimer's disease to elaborate the inhibitory effect of syringic acid (SA) on its assembly and associated neurotoxicity in aggregation conditions. Extrinsic fluorescence, Congo red adsorption, and CD spectroscopic studies, TEM, size-exclusion chromatography, and MALDI-TOF mass spectrometry analysis along with MTT and qRT-PCR assays were performed to assess the inhibitory effects of SA against tau aggregation and neurotoxicity. It was shown that SA has the tendency to control the aggregation of the tau proteins through modulating the amyloid kinetic parameters, exposure of hydrophobic residues, and structural changes. Moreover, the structures formed in the presence of SA recovered the viability of neuron-like cells (SH-SY5Y) through regulation of endoplasmic reticulum stress signaling pathway by downregulation of ATF-6, caspase-8 and caspase-3 mRNA. In conclusion, it can be suggested that SA may be used as a potential small molecule in the development of therapeutic platforms against Alzheimer's disease.