Ahmad Faraz, Singh Kunal, Das Debajyoti, Gowaikar Ruturaj, Shaw Eisha, Ramachandran Arathy, Rupanagudi Khader Valli, Kommaddi Reddy Peera, Bennett David A, Ravindranath Vijayalakshmi
1 Centre for Neuroscience, Indian Institute of Science , Bangalore, India .
2 Rush Alzheimer's Disease Center, Rush University Medical Center , Chicago, Illinois.
Antioxid Redox Signal. 2017 Dec 1;27(16):1269-1280. doi: 10.1089/ars.2016.6860. Epub 2017 Apr 12.
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.
Activity dependent but not basal translation was impaired in synaptoneurosomes from 1-month old presymptomatic APP/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.
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.
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.
已知突触功能缺陷是阿尔茨海默病（AD）认知功能障碍的基础。β-淀粉样蛋白产生的活性氧（ROS）也与AD发病机制有关。然而，尚不清楚ROS是否导致AD发病机制中出现的突触功能障碍，因此，我们研究了氧化还原信号改变是否会导致AD中的突触缺陷。
1月龄无症状APP/PS1ΔE9（APP/PS1）小鼠的突触神经小体中，活性依赖而非基础翻译受损，且这种缺陷持续至中年（9 - 10个月）。ROS生成导致突触中Akt1的氧化修饰，进而使Akt1-雷帕霉素机制性靶标（mTOR）信号传导减少，导致活性依赖的蛋白质翻译缺陷。此外，我们在AD死后大脑的突触神经小体中发现了类似的活性依赖蛋白质翻译缺失。
活性依赖的蛋白质翻译缺失在AD发病机制的早期无症状阶段就已出现。这是由ROS介导的pAkt1缺失引起的，导致突触Akt1-mTOR信号传导减少，而过表达Akt1可挽救这一现象。ROS介导的损伤仅限于突触小体，表明具有选择性。
我们证明，ROS介导的Akt1氧化修饰导致AD中的突触功能障碍，表现为活性依赖的蛋白质翻译缺失，而这对于突触可塑性和维持至关重要。促进突触处Akt1-mTOR信号传导的治疗策略可能为AD的疾病修饰治疗提供新靶点。《抗氧化与氧化还原信号》27卷，1269 - 1280页 。
