School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, Bristol, UK.
Department of Neurology, Chonnam National University Medical School, Gwangju, Republic of Korea.
Neuropharmacology. 2018 Jan;128:282-292. doi: 10.1016/j.neuropharm.2017.10.028. Epub 2017 Oct 25.
Amyloid β (Aβ) is a key mediator for synaptic dysfunction and cognitive impairment implicated in Alzheimer's disease (AD). However, the precise mechanism of the toxic effect of Aβ is still not completely understood. Moreover, there is currently no treatment for AD. Protein kinase B (PKB, also termed Akt) is known to be aberrantly regulated in the AD brain. However, its potential function as a therapeutic target for AD-associated memory impairment has not been studied. Here, we examined the role of a direct Akt activator, SC79, in hippocampus-dependent memory impairments using Aβ-injected as well as 5XFAD AD model mice. Oligomeric Aβ injections into the 3rd ventricle caused concentration-dependent and time-dependent impairments in learning/memory and synaptic plasticity. Moreover, Aβ aberrantly regulated caspase-3, GSK-3β, and Akt signaling, which interact with each other in the hippocampus. Caspase-3 and GSK-3β inhibitor ameliorated memory impairments and synaptic deficits in Aβ-injected AD model mice. We also found that pharmacological activation of Akt rescued memory impairments and aberrant synaptic plasticity in both Aβ-treated and 5XFAD mice. These results suggest that Akt could be a therapeutic target for memory impairment observed in AD.
淀粉样蛋白β（Aβ）是阿尔茨海默病（AD）中涉及突触功能障碍和认知障碍的关键介质。然而，Aβ 的毒性作用的确切机制仍不完全清楚。此外，目前尚无针对 AD 的治疗方法。蛋白激酶 B（PKB，也称为 Akt）已知在 AD 大脑中异常调节。然而，其作为 AD 相关记忆障碍的治疗靶点的潜在功能尚未得到研究。在这里，我们使用 Aβ 注射以及 5XFAD AD 模型小鼠研究了直接 Akt 激活剂 SC79 在海马依赖性记忆损伤中的作用。第三脑室中的寡聚 Aβ 注射引起学习/记忆和突触可塑性的浓度依赖性和时间依赖性损伤。此外，Aβ 异常调节了相互作用的海马中的 caspase-3、GSK-3β 和 Akt 信号通路。 caspase-3 和 GSK-3β 抑制剂可改善 Aβ 注射 AD 模型小鼠的记忆障碍和突触缺陷。我们还发现 Akt 的药理学激活可挽救 Aβ 处理和 5XFAD 小鼠的记忆障碍和异常的突触可塑性。这些结果表明 Akt 可能是 AD 中观察到的记忆障碍的治疗靶点。
