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.
Highlights
Mitochondrial damage and synaptic dysfunction are early events in the pathogenesis of Alzheimer’s disease (AD; Reddy and Beal, 2008; Hauptmann et al, 2009; Reddy, 2009; Reddy et al, 2012)
Axonal processes were selected for the quantitative analysis of mitochondrial length, density, distribution, and mobility because of their known morphologic and dynamic characteristics (Banker and Cowan, 1979; Du et al, 2010) and because of the significantly synaptic pathology of AD
There are evidence suggest that geniposide have multifaceted neuroprotective effects, such as ameliorating cholinergic deficit (Zhao et al, 2016b), increasing the expression of insulindegrading enzyme (Zhang et al, 2015) and attenuating Aβ accumulation (Lv et al, 2015), inhibiting the signaling pathway of receptor for advanced glycation end products (RAGE)-MAPK and suppressing the production of proinflammatory mediators (Lv et al, 2014b, 2015), and protecting mitochondria by recovering adenosine triphosphate (ATP) generation and mitochondrial membrane potential (Lv et al, 2014a; Zhao et al, 2016a)
Summary
Mitochondrial damage and synaptic dysfunction are early events in the pathogenesis of Alzheimer’s disease (AD; Reddy and Beal, 2008; Hauptmann et al, 2009; Reddy, 2009; Reddy et al, 2012). Synapses, which are the basic structural foundations of signal transduction in the central nervous system, form connections, and transmit chemical signals among neurons (Billups and Forsythe, 2002; Li et al, 2004). Severe structural and functional damage to synapses fundamentally cause cognitive and memory dysfunctions (Du et al, 2008; Adalbert and Coleman, 2013). Cognitive dysfunction is more strongly correlated with synaptic loss than with senile plaques, neurofibrillary tangles, neural loss, or gliosis (Pozueta et al, 2013).
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