ROS-Mediated Loss of Synaptic Akt1 Signaling Leads to Deficient Activity-Dependent Protein Translation Early in Alzheimer's Disease

Synaptic deficits are known to underlie the cognitive dysfunction seen in Alzheimer’s disease (AD). Generation of reactive oxygen species (ROS) by β-amyloid has also been implicated in AD pathogenesis. However, it is unclear if ROS contributes to synaptic dysfunction seen in AD pathogenesis and therefore, we examined if altered redox signaling could contribute to synaptic deficits in AD. Activity-dependent but not basal translation was impaired in synaptoneurosomes from 1 month old presymptomatic APP Swe /PS1ΔE9 (APP/PS1) mice, and this deficit was sustained till middle age (9-10 months). ROS generation leads to oxidative modification of Akt1 in the synapse and consequent reduction in Akt1-mTOR signaling leading to deficiency in activity dependent protein translation. Moreover, we found a similar loss of activity-dependent protein translation in synaptoneurosomes from post-mortem AD brains. Loss of activity dependent protein translation occurs presymptomatically during pathogenesis of AD. This is caused by ROS-mediated loss of pAkt1 leading to reduced synaptic Akt1-mTOR signaling and is rescued by overexpression of Akt1. ROS mediated damage is restricted to the synaptosomes indicating selectivity. We demonstrate that ROS-mediated oxidative modification of Akt1 contributes to synaptic dysfunction in AD, seen as loss of activity-dependent protein translation which is essential for synaptic plasticity and maintenance. Therapeutic strategies promoting Akt1-mTOR signaling at synapses may provide novel target(s) for disease modifying therapy in AD.