title: Reactive Oxygen Species-Mediated Loss of Synaptic Akt1 Signaling Leads to Deficient Activity-Dependent Protein Translation Early in Alzheimer's Disease.
abstract: OBJECTIVE
  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 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 presymptomatic APPSwe/PS1ΔE9 (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.
  
  
  METHODS
  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.
authors.affiliation: 1 Centre for Neuroscience, Indian Institute of Science , Bangalore, India .
authors.forename: Faraz
authors.initials: F
authors.lastname: Ahmad
authors.affiliation: 1 Centre for Neuroscience, Indian Institute of Science , Bangalore, India .
authors.forename: Kunal
authors.initials: K
authors.lastname: Singh
authors.affiliation: 1 Centre for Neuroscience, Indian Institute of Science , Bangalore, India .
authors.forename: Debajyoti
authors.initials: D
authors.lastname: Das
authors.affiliation: 1 Centre for Neuroscience, Indian Institute of Science , Bangalore, India .
authors.forename: Ruturaj
authors.initials: R
authors.lastname: Gowaikar
authors.affiliation: 1 Centre for Neuroscience, Indian Institute of Science , Bangalore, India .
authors.forename: Eisha
authors.initials: E
authors.lastname: Shaw
authors.affiliation: 1 Centre for Neuroscience, Indian Institute of Science , Bangalore, India .
authors.forename: Arathy
authors.initials: A
authors.lastname: Ramachandran
authors.affiliation: 1 Centre for Neuroscience, Indian Institute of Science , Bangalore, India .
authors.forename: Khader Valli
authors.initials: KV
authors.lastname: Rupanagudi
authors.affiliation: 1 Centre for Neuroscience, Indian Institute of Science , Bangalore, India .
authors.forename: Reddy Peera
authors.initials: RP
authors.lastname: Kommaddi
authors.affiliation: 2 Rush Alzheimer's Disease Center, Rush University Medical Center , Chicago, Illinois.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.affiliation: 1 Centre for Neuroscience, Indian Institute of Science , Bangalore, India .|3 Centre for Brain Research , Bangalore, India .
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Ravindranath
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D051379:Mice; D009473:Neuronal Plasticity; D014176:Protein Biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; C546842:MTOR protein, human; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Alzheimer's; oxidation; translation