Ligustilide alleviates neurotoxicity in SH‐SY5Y cells induced by Aβ25‐35 via regulating endoplasmic reticulum stress and autophagy

Ligustilide is a phenolic compound isolated from Asian plants of Umbelliferae family. This study was aimed at exploring the neuroprotective effects of Ligustilide from the perspective of endoplasmic reticulum stress (ERS) and autophagy. The Alzheimer's disease (AD) cell models were constructed by SH‐SY5Y cell line, which was exposed to 20 μM Aβ 25‐35 . CCK‐8 was used to evaluate the cell viability of Ligustilide on AD cell model. Hoechst staining and LysoTracker Red were used to test the cell apoptosis and Lysosome function, respectively. ERS in living cells were detected by Thioflavin T. The expression of autophagy‐related proteins (LC3B‐II/I, P62/SQSTM1, Beclin1, and Atg5), ERS marker proteins (PERK, GRP78, and CHOH), and apoptosis proteins (Bax, Bcl‐2, and Caspase‐12) were analyzed by Western blot analyses. Aβ 25‐35 could induce ERS and autophagy in a time‐dependent manner in SH‐SY5Y cells. We demonstrated that Ligustilide significantly decreased the rate of apoptosis, and improved the viability of cells. Simultaneously, Ligustilide effectively modulated ERS via inhibiting the over‐activation of GRP78/PERK/CHOP signaling pathway. In addition, Ligustilide alleviated the accumulation of autophagy vacuoles, reduced the ratio of LC3B‐II/I and the level of P62/SQSTM1. Ligustilide significantly up‐regulated lysosomal acidity and the expression of Cathepsin D (CTSD). Ligustilide could rescue lysosomal function to promote autophagy flux and inhibit the over‐activation of ERS. This finding may contribute to the development of new therapeutic strategies for AD.