377 - Novel Anti-Oxidant V2O5 Nanowires Prevent Spine Loss in Primary Cortical Neurons Derived from a Mouse Model of Alzheimer′s Disease

Abstract

Alzheimer’s disease (AD) is an age-associated neurodegenerative disorder. However, the pathogenesis begins 2-3 decades before the appearance of symptoms, wherein neuronal function is compromised, particularly at the synapse. In the absence of promising therapeutic approaches, we need better understanding of the functional and structural changes that occur in presymptomatic stages to successfully alter progression of AD. A major causative role in pathogenesis of AD is attributed to Aβ42, a peptide formed by proteolytic processing of amyloid precursor protein (APP). Despite intensive research on the role of Aβ42 in AD, its primary target and mechanism of action remain elusive. We cultured primary cortical neurons from APPswe/PS1ΔE9 (APP/PS1) mice and wild type (WT) littermates. Mushroom spine loss was detected at DIV (days in-vitro)-15, one of the earliest structural changes observed in APP/PS1 neurons. These neurons showed significantly greater accumulation of Aβ42 at this time-point. Aβ42 is known to generate reactive oxygen species (ROS), and significantly higher endogenous ROS levels were detected in APP/PS1 neurons compared to WT neurons. F-actin (filamentous actin) is crucial for the formation and support of mushroom spine structure, and its levels are susceptible to ROS. Therefore, we examined F-actin levels in neurons using Phalloidin staining. Decreased staining was observed in APP/PS1 neurons, suggesting lowereing of F-actin. To test whether decreasing oxidative stress can prevent spine loss by restoring F-actin levels, we used V2O5 nanowires. The nanowires scavenge ROS by engaging in cyclic reactions to reduce H2O2 using glutathione (GSH) as an electron donor. This enzyme-like activity allows low intracellular concentrations of V2O5 nanowires to protect cells from oxidative stress for long periods of time. Our results show that V2O5 nanowires decrease ROS levels in APP/PS1 neurons to that observed in WT, as well as reversing F-actin loss. Moreover, this also prevents the loss of mushroom spines in APP/PS1 neurons. Our results demonstrate the use of V2O5 nanowires as a novel approach to reduce oxidative stress and reverse the consequent impairment in APP/PS1 primary cortical neurons.