Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease, which is characterized by extracellular senile plaque deposits, intracellular neurofibrillary tangles, and neuronal apoptosis. Amyloid-β (Aβ) plays a critical role in AD that may cause oxidative stress and downregulation of CREB/BDNF signaling. Anti-Aβ effect has been discussed as a potential therapeutic strategy for AD. This study aimed to identify the amelioration of procyanidins extracted from lotus seedpod (LSPC) on Aβ-induced damage with associated pathways for AD treatment. Rat pheochromocytoma (PC12) cells incubated with Aβ 25–35 serve as an Aβ damage model to evaluate the effect of LSPC in vitro. Our findings illustrated that LSPC maintained the cellular morphology from deformation and reduced apoptosis rates of cells induced by Aβ 25–35. The mechanisms of LSPC to protect cells from Aβ-induced damage were based on its regulation of oxidation index and activation of CREB/BDNF signaling, including brain-derived neurotrophic factor (BDNF) and phosphorylation of cAMP-responsive element-binding (CREB), protein kinase B (also known as AKT), and the extracellular signal-regulated kinase (ERK). Of note, by high-performance liquid chromatography-tandem mass spectroscopy (LC-MS/MS), several metabolites were detected to accumulate in vivo, part of which could take primary responsibility for the amelioration of Aβ-induced damage on PC12 cells. Taken together, our research elucidated the effect of LSPC on neuroprotection through anti-Aβ, indicating it as a potential pretreatment for Alzheimer's disease.
Highlights
Alzheimer’s disease (AD), a progressive neurodegenerative disease, is characterized by extracellular senile plaque deposits, intracellular neurofibrillary tangles, and neuronal apoptosis
AKT and extracellular signal-regulated kinase (ERK) are two key kinases in modulating brain-derived neurotrophic factor (BDNF) transcription by activating phosphorylation of cAMP-responsive element-binding (CREB) [6, 7], both of Oxidative Medicine and Cellular Longevity which could be attenuated by Aβ [8, 9]
Cell Counting Kit-8 (CCK-8) was purchased from Dojindo (Japan); anti-BDNF antibody was purchased from Elabscience (China); anti-CREB antibody, anti-phospho-CREB (Ser133) antibody, anti-AKT antibody, anti-phospho-AKT (Ser473) antibody, anti-ERK1/2 antibody, anti-phospho-ERK1/2 (Thr202/Tyr204) antibody, and anti-GAPDH antibody were purchased from cell signaling; LY294002 inhibitor for PI3K and PD98059 inhibitor for ERK1/2 were purchased from Selleckchem; lactate dehydrogenase (LDH), superoxide dismutase (SOD), and malonialdehyde (MDA) were from Nanjing Jiancheng Bioengineering Institute (Nanjing, China); gallic acid was purchased from DRE; procyanidin dimer B (PDB) was purchased from Fluka Co.; epigallocatechin gallate (ECG) was purchased from
Summary
Alzheimer’s disease (AD), a progressive neurodegenerative disease, is characterized by extracellular senile plaque deposits, intracellular neurofibrillary tangles, and neuronal apoptosis. AKT ( known as protein kinase B) and extracellular signal-regulated kinase (ERK) are two key kinases in modulating brain-derived neurotrophic factor (BDNF) transcription by activating phosphorylation of cAMP-responsive element-binding (CREB) [6, 7], both of Oxidative Medicine and Cellular Longevity which could be attenuated by Aβ [8, 9]. The underlying mechanism of Aβ on CREB/BDNF signaling is possible that Aβ inhibits the activation of AKT and ERK, resulting in decreasing phosphorylation of CREB, the upstream of BDNF [13], and attenuating both transcriptions of BDNF mRNA and expression of BDNF protein [14]. Simulating CREB/BDNF signaling against Aβ-induced damage is a promising therapeutic tactic for AD. BDNF and oxidative stress have an interactive influence in vivo [18, 19] so nature compounds are beneficial for AD treatment, which can modulate oxidative stress and CREB/BDNF signaling
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