Schools of Physiology and Pharmacology and Clinical Sciences, University of Bristol, Bristol, UK.
J Alzheimers Dis. 2011;25(3):455-62. doi: 10.3233/JAD-2011-110011.
Expression of the neuropeptide galanin is known to be upregulated in the brain of patients with Alzheimer's disease (AD). We and others have shown that galanin plays a neuroprotective role in a number of excitotoxic injury paradigms, mediated by activation of the second galanin receptor subtype (GAL2). In the present study, we investigated whether galanin/GAL2 plays a similar protective role against amyloid-β(Aβ) toxicity. Here we report that galanin or the GAL2/3-specific peptide agonist Gal2-11, both equally protect primary dispersed mouse wildtype (WT) neonatal hippocampal neurons from 250 nM Aβ1-42 toxicity in a dose dependent manner. The amount of Aβ1-42 induced cell death was significantly greater in mice with loss-of-function mutations in galanin (Gal-KO) or GAL2 (GAL2-MUT) compared to strain-matched WT controls. Conversely, cell death was significantly reduced in galanin over-expressing (Gal-OE) transgenic mice compared to strain-matched WT controls. Exogenous galanin or Gal2-11 rescued the deficits in the Gal-KO but not the GAL2-MUT cultures, confirming that the protective effects of endogenous or exogenous galanin are mediated by activation of GAL2. Despite the high levels of endogenous galanin in the Gal-OE cultures, the addition of exogenous 100 nM or 50 nM galanin or 100 nM Gal2-11 further significantly reduced cell death, implying that GAL2-mediated neuroprotection is not at maximum in the Gal-OE mice. These data further support the hypothesis that galanin over-expression in AD is a neuroprotective response and imply that the development of a drug-like GAL2 agonist might reduce the progression of symptoms in patients with AD.
神经肽甘丙肽的表达已知在阿尔茨海默病（AD）患者的大脑中上调。我们和其他人已经表明，甘丙肽在许多兴奋性毒性损伤模型中发挥神经保护作用，这是通过激活第二甘丙肽受体亚型（GAL2）介导的。在本研究中，我们研究了甘丙肽/GAL2 是否对淀粉样蛋白-β（Aβ）毒性具有类似的保护作用。在这里，我们报告甘丙肽或 GAL2/3 特异性肽激动剂 Gal2-11 都能以剂量依赖的方式同等保护原代分散的野生型（WT）新生小鼠海马神经元免受 250 nM Aβ1-42 毒性的侵害。与匹配的 WT 对照相比，甘丙肽功能丧失突变（Gal-KO）或 GAL2（GAL2-MUT）的小鼠中 Aβ1-42 诱导的细胞死亡量显着增加。与匹配的 WT 对照相比，甘丙肽过表达（Gal-OE）转基因小鼠的细胞死亡显着减少。外源性甘丙肽或 Gal2-11 挽救了 Gal-KO 但不能挽救 GAL2-MUT 培养物的缺陷，证实内源性或外源性甘丙肽的保护作用是通过激活 GAL2 介导的。尽管 Gal-OE 培养物中存在高水平的内源性甘丙肽，但添加外源性 100 nM 或 50 nM 甘丙肽或 100 nM Gal2-11 进一步显着降低了细胞死亡，这意味着在 Gal-OE 小鼠中，GAL2 介导的神经保护作用未达到最大值。这些数据进一步支持了甘丙肽在 AD 中过度表达是一种神经保护反应的假设，并暗示开发类似药物的 GAL2 激动剂可能会减缓 AD 患者症状的进展。
