Neuroscience Group, Research Institute Hospital 12 de Octubre, Madrid, Spain.
J Alzheimers Dis. 2011;24 Suppl 2:17-25. doi: 10.3233/JAD-2011-102070.
Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with senile amyloid-β (Aβ) plaques, neuronal death, and cognitive decline. Neurogenesis in the adult hippocampus, which is notably affected by progressive neurodegeneration and Aβ pathology, is implicated in learning and memory regulation. Human postmortem brains of AD patients and AβPP/PS1 double transgenic mice show increased neurodegeneration. Leptin, an adipose-derived hormone, promotes neurogenesis in the adult hippocampus, but the way in which this process occurs in the AD brain is still unknown. Thus, we sought to determine if leptin stimulated the proliferation of neuronal precursors in AβPP/PS1 mice. We estimated the number proliferating hippocampal cells after intracerebroventricular administration of a lentiviral vector encoding leptin. After 3 months of treatment with leptin we observed an increase in the number of BrdU-positive cells in the subgranular zone of the dentate gyrus, as shown by morphometric analysis. This increase resulted mainly from an increased proliferation of neuronal precursors. Additionally, leptin led to an attenuation of Aβ-induced neurodegeneration, as revealed by Fluoro-Jade staining. Our results suggest that in AβPP/PS1 mice, leptin exerts changes resembling acute neurotrophic and neuroprotective effects. These effects could serve as the basis for the design of future treatment strategies in AD.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，与老年淀粉样β（Aβ）斑块、神经元死亡和认知能力下降有关。成年海马体中的神经发生，明显受到进行性神经退行性变和 Aβ病理学的影响，与学习和记忆调节有关。AD 患者的人类死后大脑和 AβPP/PS1 双转基因小鼠显示出神经退行性变增加。瘦素是一种脂肪衍生的激素，可促进成年海马体中的神经发生，但在 AD 大脑中发生这种过程的方式仍不清楚。因此，我们试图确定瘦素是否刺激 AβPP/PS1 小鼠中的神经元前体细胞增殖。我们估计了通过立体定向脑室内注射编码瘦素的慢病毒载体后海马细胞的增殖数量。经过 3 个月的瘦素治疗，我们通过形态计量分析观察到齿状回颗粒下区 BrdU 阳性细胞数量增加。这种增加主要是由于神经元前体细胞的增殖增加所致。此外，瘦素导致 Fluoro-Jade 染色显示的 Aβ 诱导的神经退行性变减弱。我们的结果表明，在 AβPP/PS1 小鼠中，瘦素发挥的作用类似于急性神经营养和神经保护作用。这些作用可以为 AD 的未来治疗策略设计提供基础。
