Abstract
Improving mitochondrial dysfunction and inhibiting apoptosis has always been regarded as a treatment strategy for Alzheimer’s disease (AD). Isoforsythiaside (IFY), a phenylethanoid glycoside isolated from the dried fruit of Forsythia suspensa, displays antioxidant activity. This study examined the neuroprotective effects of IFY and its underlying mechanisms. In the L-glutamate (L-Glu)-induced apoptosis of HT22 cells, IFY increased cell viability, inhibited mitochondrial apoptosis, and reduced the intracellular levels of reactive oxygen species (ROS), caspase-3, -8 and -9 after 3 h of pretreatment and 12–24 h of co-incubation. In the APPswe/PSEN1dE9 transgenic (APP/PS1) model, IFY reduced the anxiety of mice, improved their memory and cognitive ability, reduced the deposition of beta amyloid (Aβ) plaques in the brain, restrained the phosphorylation of the tau protein to form neurofibrillary tangles, inhibited the level of 4-hydroxynonenal in the brain, and improved phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway-related mitochondrial apoptosis. In Aβ1-42-induced U251 cells, IFY relieved the mitochondrial swelling, crest ruptures and increased their electron density after 3 h of pretreatment and 18–24 h of co-incubation. The improved cell viability and mitochondrial function after IFY incubation was blocked by the synthetic PI3K inhibitor LY294002. Taken together, these results suggest that IFY exerts a protective effect against AD by enhancing the expression levels of anti-apoptosis proteins and reducing the expression levels of pro-apoptosis proteins of B-cell lymphoma-2 (BCL-2) family members though activating the PI3K/AKT pathway.
Highlights
As one of the chronic neurodegenerative disease, Alzheimer’s disease (AD) attacks more and more elderly people [1], and is characterized by memory loss and cognitive decline [2]
Two significant pathological features—senile plaques formed by insoluble beta amyloid (Aβ) deposition and neurofibrillary tangles (NFTs)—consist of the highly phosphorylated tau protein, and have been noted in AD patients’ brains [3]
Aβ has been found in the brain mitochondria of AD patients and AD mice [8] and interacts with the mitochondrial matrix protein-binding alcohol dehydrogenase protein (ABAD), causing oxidative damage to mitochondria [9]
Summary
As one of the chronic neurodegenerative disease, Alzheimer’s disease (AD) attacks more and more elderly people [1], and is characterized by memory loss and cognitive decline [2]. There is no effective drug that can slow or prevent the neuronal damage caused by AD [1], which emphasizes the need to search for alternative agents. Forsythoside A, one of the major component of Forsythia suspensa, can improve the learning ability and memory of SAMP8 mice by inhibiting oxidative stress and reducing inflammatory factors [18]. Forsythoside A acts as a neuroprotective agent by inhibiting the expression of acetylcholinesterase and caspase-3 in Aβ25-35-damaged PC12 cells [19], and prevents Aβ25-35-induced apoptosis through the cannabinoid receptor 1 (CB1R)-dependent nuclear factor-κB (NF-κB) pathway in hippocampal slices [20]. Further data confirmed that the neuroprotection of IFY is related to its modulation on mitochondria apoptosis via PI3K/AKT signaling. Our data provided the experimental evidence for IFY as a potential agent in clinical applications for inhibiting or reversing AD progression
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