Ioudina Marina, Uemura Etsuro
Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA.
Exp Neurol. 2003 Dec;184(2):923-9. doi: 10.1016/S0014-4886(03)00314-5.
Amyloid beta-peptide (Abeta) contributes to the pathogenesis of Alzheimer's disease (AD), causing neuronal death through apoptosis. In this study, the neuroprotective role of small peptides, Gly-Pro-Glu (GPE), Gly-Glu (GE), Gly-Pro-Asp (GPD), and Gly-Pro-Arg (GPR) were examined against Abeta-induced toxicity in cultured rat hippocampal neurons. We report here that GPR (10-100 microM) prevented Abeta-mediated increase in lactate dehydrogenase (LDH) release and Abeta inhibition of MTT reduction, even in neurons that were pre-exposed to Abeta for 24 or 48 h. Since GPR prevented Abeta inhibition of MTT reduction, the anti-apoptotic effect of GPR was studied by examining activation of caspase-3 and expression of p53 protein. Caspase-3 was significantly activated by 20 microM Abeta25-35 and 5 microM Abeta1-40, but GPR effectively prevented the Abeta-mediated activation of caspase-3. Similarly, Abeta increased numbers of p53-positive cells, but GPR prevented this Abeta effect. Our findings suggest that GPR can rescue cultured rat hippocampal neurons from Abeta-induced neuronal death by inhibiting caspase-3/p53-dependent apoptosis.
淀粉样β肽（Aβ）在阿尔茨海默病（AD）的发病机制中起作用，通过凋亡导致神经元死亡。在本研究中，检测了小肽甘氨酰-脯氨酰-谷氨酸（GPE）、甘氨酰-谷氨酸（GE）、甘氨酰-脯氨酰-天冬氨酸（GPD）和甘氨酰-脯氨酰-精氨酸（GPR）对培养的大鼠海马神经元中Aβ诱导毒性的神经保护作用。我们在此报告，即使在预先暴露于Aβ 24或48小时的神经元中，GPR（10 - 100微摩尔）也能阻止Aβ介导的乳酸脱氢酶（LDH）释放增加以及Aβ对MTT还原的抑制。由于GPR阻止了Aβ对MTT还原的抑制，通过检测半胱天冬酶-3的激活和p53蛋白的表达来研究GPR的抗凋亡作用。20微摩尔的Aβ25 - 35和5微摩尔的Aβ1 - 40可显著激活半胱天冬酶-3，但GPR有效地阻止了Aβ介导的半胱天冬酶-3激活。同样，Aβ增加了p53阳性细胞的数量，但GPR阻止了这种Aβ效应。我们的研究结果表明，GPR可通过抑制半胱天冬酶-3/p53依赖性凋亡，使培养的大鼠海马神经元从Aβ诱导的神经元死亡中获救。
