Varma R, Chai Y, Troncoso J, Gu J, Xing H, Stojilkovic S S, Mattson M P, Haughey N J
Department of Neurology, Johns Hopkins, University School of Medicine, Meyer 6-109, 600 N. Wolfe St., Baltimore, MD 21287, USA.
Neuromolecular Med. 2009;11(2):63-75. doi: 10.1007/s12017-009-8073-2. Epub 2009 Jun 27.
Overproduction of the beta-amyloid fragment 1-42 (A beta(1-42)) is thought to contribute to synaptic dysfunction and neuronal death in Alzheimer's disease. Mounting evidence suggests that purinergic receptors play critical roles in synaptic plasticity and neuronal survival, but the potential involvement of these receptors in A beta(1-42)-induced synaptic dysfunction and neuronal death has not been addressed. Here we report that A beta(1-42) promoted accumulation of the calcium-permeable purinergic receptor P2X4 in neurons. We also report evidence that A beta(1-42) induced a caspase-3-mediated cleavage of the receptor that slowed channel closure times and prevented agonist-induced internalization of the receptor. Molecular interference to reduce the expression of P2X4 in primary rodent neurons attenuated A beta(1-42)-induced neuronal death while induced expression of P2X4 in a neuronal cell line that does not normally express P2-receptors enhanced the toxic effect of A beta(1-42). Together these findings suggest that A beta(1-42)-induced synaptic dysfunction and neuronal death may involve perturbations in P2X4 purinergic receptors.
β-淀粉样蛋白片段1-42（Aβ(1-42)）的过度产生被认为与阿尔茨海默病中的突触功能障碍和神经元死亡有关。越来越多的证据表明嘌呤能受体在突触可塑性和神经元存活中起关键作用，但这些受体在Aβ(1-42)诱导的突触功能障碍和神经元死亡中的潜在参与尚未得到探讨。在此我们报告，Aβ(1-42)促进了神经元中钙通透性嘌呤能受体P2X4的积累。我们还报告了证据表明，Aβ(1-42)诱导了受体的半胱天冬酶-3介导的切割，这减缓了通道关闭时间并阻止了激动剂诱导的受体内化。在原代啮齿动物神经元中减少P2X4表达的分子干扰减弱了Aβ(1-42)诱导的神经元死亡，而在通常不表达P2受体的神经元细胞系中诱导P2X4表达则增强了Aβ(1-42)的毒性作用。这些发现共同表明，Aβ(1-42)诱导的突触功能障碍和神经元死亡可能涉及P2X4嘌呤能受体的扰动。
