Gourmaud Sarah, Mouton-Liger François, Abadie Claire, Meurs Eliane F, Paquet Claire, Hugon Jacques
Inserm UMR-S 942, Paris, France.
Brain and Spine Institute, Paris, France.
J Alzheimers Dis. 2016 Oct 18;54(4):1659-1670. doi: 10.3233/JAD-160509.
In Alzheimer's disease (AD), the amyloid cascade hypothesis proposes that amyloid-beta (Aβ) neurotoxicity leads to neuroinflammation, synaptic loss, and neuronal degeneration. In AD patients, anti-amyloid immunotherapies did not succeed because they were possibly administered late in AD progression. Modulating new targets associated with Aβ toxicity, such as PKR (double-stranded RNA dependent kinase), and JNK (c-Jun N-terminal kinase) is a major goal for neuroprotection. These two pro-apoptotic kinases are activated in AD brains and involved in Aβ production, tau phosphorylation, neuroinflammation, and neuronal death. In HEK cells transfected with siRNA directed against PKR, and in PKR knockout (PKR-/-) mice neurons, we showed that PKR triggers JNK activation. Aβ-induced neuronal apoptosis, measured by cleaved PARP (Poly ADP-ribose polymerase) and cleaved caspase 3 levels, was reduced in PKR-/- neurons. Two selective JNK inhibitory peptides also produced a striking reduction of Aβ toxicity. Finally, the dual inhibition of PKR and JNK nearly abolished Aβ toxicity in primary cultured neurons. These results reveal that dual kinase inhibition can afford neuroprotection and this approach is worth being tested in in vivo AD and oxidative stress models.
在阿尔茨海默病（AD）中，淀粉样蛋白级联假说提出，β-淀粉样蛋白（Aβ）的神经毒性会导致神经炎症、突触丧失和神经元变性。在AD患者中，抗淀粉样蛋白免疫疗法未获成功，因为它们可能在AD病程后期才应用。调节与Aβ毒性相关的新靶点，如PKR（双链RNA依赖性激酶）和JNK（c-Jun氨基末端激酶），是神经保护的主要目标。这两种促凋亡激酶在AD大脑中被激活，并参与Aβ生成、tau蛋白磷酸化、神经炎症和神经元死亡。在转染了针对PKR的小干扰RNA（siRNA）的人胚肾（HEK）细胞以及PKR基因敲除（PKR-/-）小鼠的神经元中，我们发现PKR可触发JNK激活。通过裂解的聚（ADP-核糖）聚合酶（PARP）和裂解的半胱天冬酶3水平测定，PKR-/-神经元中Aβ诱导的神经元凋亡减少。两种选择性JNK抑制肽也显著降低了Aβ毒性。最后，对PKR和JNK的双重抑制几乎消除了原代培养神经元中的Aβ毒性。这些结果表明，双重激酶抑制可提供神经保护，这种方法值得在AD体内模型和氧化应激模型中进行测试。
