丙酮酸盐拮抗β-淀粉样蛋白寡聚体神经毒性的保护作用与机制研究

阿尔茨海默病（AD）是一种神经退行性疾病，以进行性记忆减退和认知功能障碍为主要临床症状，但AD的病因和发病机制复杂,目前AD的确切病因尚不清楚,研究表明在AD出现神经变性前的早期记忆功能障碍中，可溶性β-淀粉样蛋白(Aβ)寡聚体发挥了重要的作用，已成为治疗AD的热门靶点。本研究拟用海马组织切片培养体外模拟AD环境和建立大鼠AD模型两种实验手段，明确丙酮酸盐对Aβ寡聚体所诱导的神经突触传递抑制的保护作用，以及明确丙酮酸盐可以降低AD大鼠的神经细胞死亡率和改善认知功能障碍，探讨丙酮酸盐神经保护作用的可能机制。首次提出丙酮酸盐可通过抗氧化作用抑制磷酸酯酶2A（PP2A）活化,间接增加磷酸化Ca2+/钙调蛋白依赖性蛋白激酶Ⅱ（CaMKⅡ）水平，从而发挥丙酮酸盐的神经保护作用。研究结果对进一步明确丙酮酸盐改善AD患者认知功能障碍的本质具有重要意义，有助于在基础理论和临床治疗AD中取得新突破。

Recent progress in the field of Alzheimer's disease (AD) has provided evidence that Aβ oligomers cause the inhibition of synaptic transmission preceding neuronal cell death. Aβ oligomers inhibit long-term potentiation (LTP), a classic experimental paradigm for memory and synaptic plasticity. Therapeutic strategies developed to interfere with Aβ oligomers deposition and clearance have shown initial benefit in AD patients and rodent models. .Pyruvate, an intermediate metabolite of the glycolysis cycle, is a cell protective agent and administration of pyruvate protects neurons against the neurotoxicity of hydrogen peroxide in vitro and Aβ-induced neuronal death. However, whether pyruvate works protectively against the suppression of the synaptic transmission induced by Aβ oligomers is unknown. .This study will use the slice culture system to investigate the effects of pyruvate on the Aβ oligomer-induced inhibition of LTP, and use AD pathological model to investigate the effects of pyruvate on the Aβ oligomer -induced neurodegeneration and cognitive impairement. We propose that pyruvate could prevent the Aβ oligomer-induced inhibition of LTP (in the short term of AD) by the re-autophosphorylation of CaMKⅡ through PP2A inactivation, and pyruvate also could reduce neurodegenneration (in the long term of AD) induced by Aβ oligomer and improve the congnitive function through preservation of the NAD+ levels and ATP levels. The reduction of ROS production is considered to be the upstream mechanism of this observed pyruvate protection. Accordingly, pyruvate may be clinically applied to the the early stage of Alzheimer's disease patients who suffered from amnesia in which synaptic function will be mainly compromised with minimum neuronal cell loss. Considering the low cost and small degree of side effects of pyruvate, its application as a neuroprotective drug is expectted to achieve an excellent cost performance in clinical practice of AD.