Galangin decreases p‑tau, Aβ42 and β‑secretase levels, and suppresses autophagy in okadaic acid‑induced PC12 cells via an Akt/GSK3β/mTOR signaling‑dependent mechanism

Abstract

Okadaic acid (OA)-induced neurotoxicity may be considered a novel tool used to study Alzheimer's disease (AD) pathology, and may be helpful in the development of a novel therapeutic approach. It has been reported that galangin inhibits β-site amyloid precursor protein-cleaving enzyme 1 expression, which is a key enzyme for amyloid β (Aβ) generation and is a potential drug candidate for AD therapy. However, further studies are required to confirm its neuroprotective effects in other AD models. The present study aimed to explore the neuroprotective effects of galangin on OA-induced neurotoxicity in PC12 cells. The cells were divided into the following groups: Control group, model group (175 nM OA for 48 h) and galangin groups (0.25, 0.5 and 1 µg/ml). Beclin-1, phosphorylated (p)-protein kinase B (Akt), p-glycogen synthase kinase (GSK)3β and p-mechanistic target of rapamycin (mTOR) expression was also measured in the following PC12 cell groups: Control group, model group, 3-methyladenine group (5 nM), rapamycin group (100 nM) and galangin group (1 µg/ml). The levels of β-secretase, Aβ 42 and p-tau were detected by ELISA, Beclin-1 expression was examined by immunohistochemistry and the protein expression levels of p-Akt, p-mTOR p-GSK3β, and Beclin-1 were detected by western blotting. Galangin treatment enhanced cell viability in cells treated with OA, and decreased β-secretase, Aβ 42 and p-tau levels. In addition, it suppressed Beclin-1 and p-GSK3β expression, but promoted p-Akt and p-mTOR expression by regulating the Akt/GSK3β/mTOR pathway. These results indicated that galangin protected PC12 cells from OA-induced cytotoxicity and inhibited autophagy via the Akt/GSK3β/mTOR pathway, thus suggesting that it may be considered a potential therapeutic agent for AD.

Prokineticin 2 (PK2) Rescues Cardiomyocytes from High Glucose/High Palmitic Acid-Induced Damage by Regulating the AKT/GSK3β Pathway In Vitro

“…Therefore, we deduced that PK2 is responsible for improvements in oxidative stress and apoptosis in cardiomyocytes exposed to high glucose/high palmitic acid through stimulating PKR, but the underlying mechanism is still unknown. AKT has been shown to be involved in cardiovascular functions linked with cell survival, growth, proliferation, and angiogenesis by inactivating its downstream target GSK3β [44][45][46]. Dariushnejad et al [47] reported that the activation of the AKT signalling pathway in the hearts of high-fat diet-and streptozotocin-induced diabetic rats has a beneficial effect on apoptosis and angiogenesis.…”

Oxyphylla A ameliorates cognitive deficits and alleviates neuropathology via the Akt-GSK3β and Nrf2-Keap1-HO-1 pathways in vitro and in vivo murine models of Alzheimer's disease

“…GSK3β has been shown to coimmunoprecipitate with Presenilin-1, which is a critical gene involved in the generation of Aβ and early onset AD [42] , [43] . In both the pathological and physiological state, active GSK3β has the ability to phosphorylate over 20 sites on Tau protein, leading to the formation of NFTs [44] , [45] . Several studies have shown that inhibition of GSK3β can induce the activation of Nrf2 under oxidative stress conditions in AD [46] , [47] , [48] .…”

Mitochondria-associated membranes (MAMs): a potential therapeutic target for treating Alzheimer’s disease

“…Autophagy can effectively clear the damaged/dead cells and long-lived protein aggregates, in normal neurons [132]. Autophagic regulation is comprised of two complicated signaling transduction pathways including the mTOR-dependent and mTOR-independent mechanisms, both of which are involved in the AD pathology [133,134]. Researchers have hypothesized that impaired autophagy significantly reduces the clearance of Aβ and tau deposition in the brain of AD patients and animal models [135].…”