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

Ahmad, Faraz and Singh, Kunal and Das, Debajyoti and Gowaikar, Ruturaj and Shaw, Eisha and Ramachandran, Arathy and Rupanagudi, Khader Valli and Kommaddi, Reddy Peera and Bennett, David A and Ravindranath, Vijayalakshmi (2017) Reactive Oxygen Species-Mediated Loss of Synaptic Akt1 Signaling Leads to Deficient Activity-Dependent Protein Translation Early in Alzheimer's Disease. In: ANTIOXIDANTS & REDOX SIGNALING, 27 (16). pp. 1269-1280.

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Abstract

Aims: Synaptic deficits are known to underlie the cognitive dysfunction seen in Alzheimer's disease (AD). Generation of reactive oxygen species (ROS) by beta-amyloid has also been implicated in AD pathogenesis. However, it is unclear whether ROS contributes to synaptic dysfunction seen in AD pathogenesis and, therefore, we examined whether altered redox signaling could contribute to synaptic deficits in AD. Results: Activity dependent but not basal translation was impaired in synaptoneurosomes from 1-month old pre-symptomatic APP(Swe)/PS1 Delta E9 (APP/PS1) mice, and this deficit was sustained till middle age (MA, 9-10 months). ROS generation leads to oxidative modification of Akt1 in the synapse and consequent reduction in Akt1-mechanistic target of rapamycin (mTOR) signaling, leading to deficiency in activity-dependent protein translation. Moreover, we found a similar loss of activity-dependent protein translation in synaptoneurosomes from postmortem AD brains. Innovation: Loss of activity-dependent protein translation occurs presymptomatically early in the 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. Conclusions: We demonstrate that ROS-mediated oxidative modification of Akt1 contributes to synaptic dysfunction in AD, seen as loss of activity-dependent protein translation that 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. Antioxid. Redox Signal. 27, 1269-1280.

Item Type:	Journal Article
Publication:	ANTIOXIDANTS & REDOX SIGNALING
Additional Information:	Copy right for this article belongs to the MARY ANN LIEBERT, INC, 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA
Department/Centre:	Division of Biological Sciences > Centre for Neuroscience
Date Deposited:	11 Nov 2017 07:21
Last Modified:	11 Nov 2017 07:21
URI:	http://eprints.iisc.ac.in/id/eprint/58183

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