Geniposide Alleviates Amyloid-Induced Synaptic Injury by Protecting Axonal Mitochondrial Trafficking

Abstract

Synaptic and mitochondrial pathologies are early events in the progression of Alzheimer's disease (AD). Normal axonal mitochondrial function and transport play crucial roles in maintaining synaptic function by producing high levels of adenosine triphosphate and buffering calcium. However, there can be abnormal axonal mitochondrial trafficking, distribution, and fragmentation, which are strongly correlated with amyloid-β (Aβ)-induced synaptic loss and dysfunction. The present study examined the neuroprotective effect of geniposide, a compound extracted from gardenia fruit in Aβ-treated neurons and an AD mouse model. Geniposide alleviated Aβ-induced axonal mitochondrial abnormalities by increasing axonal mitochondrial density and length and improving mitochondrial motility and trafficking in cultured hippocampal neurons, consequently ameliorating synaptic damage by reversing synaptic loss, addressing spine density and morphology abnormalities, and ameliorating the decreases in synapse-related proteins in neurons and APPswe/PS1dE9 mice. These findings provide new insights into the effects of geniposide administration on neuronal and synaptic functions under conditions of Aβ enrichment.

A Review on the Phytochemistry, Pharmacology, Pharmacokinetics and Toxicology of Geniposide, a Natural Product

“…GS treatment (12.5, 25, 50 mg/kg in vivo, 2.5, 5, 10 μM in vitro) demonstrated the protection against the above dysfunction through attenuating axonal mitochondrial fragmentation, trafficking impairments and reactive oxygen species (ROS) elevation; protecting synaptic loss, abnormal spine density and morphology; and ameliorating the decrease in synapse-related proteins. The findings indicated GS as a potential drug to cease and prevent the early progression of AD [ 168 ].…”

Comparative pharmacokinetic study of the components of Jia‐Wei‐Kai‐Xin‐San in normal and vascular dementia rats by ultra‐fast liquid chromatography coupled with tandem mass spectrometry

“…Geniposide is iridoid glycoside, which can be converted to genipin by β‐glucosidase of commensal bacteria in gut. Both geniposide and its metabolite genipin possess the effect of protecting neuron from injuries induced by Aβ, oxidant, inflammation, and brain ischemia . Therefore, the decreased bioavailability of geniposide might be due to the accelerated biotransformation in VD model rats.…”

Differential effect of amyloid beta peptides on mitochondrial axonal trafficking depends on their state of aggregation and binding to the plasma membrane

“…Analysis of the brain tissue from these mice revealed increased levels of BDNF and synaptic proteins, and enhanced cellular energetics associated with cognitive protection. Similar, restoration of axonal trafficking using antioxidants, by increasing the acetylation of anti-oxidant protein peroxdiredoxin1 by HDAC6 inhibition or by treatment with geniposide, a pharmacologically active component purified from gardenia fruit, resulted in reduced levels of ROS and Ca 2+ , and synaptic protection in multiple cellular and mouse models of AD (Choi et al, 2017; Guo et al, 2013; Lv et al, 2015; Reddy et al, 2012; Yu et al, 2016; Zhang et al, 2016a). Since mitochondrial trafficking inhibition in neurons is not specific to AD (De Vos and Hafezparast, 2017; Morfini et al, 2009; Trushina et al, 2004), the development of therapeutic strategies to restore axonal trafficking could be beneficial for multiple neurodegenerative diseases.…”