Van Kampen Jackalina M, Kay Denis G
Neurodyn Inc., Charlottetown, PE, Canada.
Dept. Biomedical Science, University of Prince Edward Island, Charlottetown, PE, Canada.
PLoS One. 2017 Aug 24;12(8):e0182896. doi: 10.1371/journal.pone.0182896. eCollection 2017.
Progranulin (PGRN) is a multifunctional protein that is widely expressed throughout the brain, where it has been shown to act as a critical regulator of CNS inflammation and also functions as an autocrine neuronal growth factor, important for long-term neuronal survival. PGRN has been shown to activate cell signaling pathways regulating excitoxicity, oxidative stress, and synaptogenesis, as well as amyloidogenesis. Together, these critical roles in the CNS suggest that PGRN has the potential to be an important therapeutic target for the treatment of various neurodegenerative disorders, particularly Alzheimer's disease (AD). AD is the leading cause of dementia and is marked by the appearance of extracellular plaques consisting of aggregates of amyloid-β (Aβ), as well as neuroinflammation, oxidative stress, neuronal loss and synaptic atrophy. The ability of PGRN to target multiple key features of AD pathophysiology suggests that enhancing its expression may benefit this disease. Here, we describe the application of PGRN gene transfer using in vivo delivery of lentiviral expression vectors in a transgenic mouse model of AD. Viral vector delivery of the PGRN gene effectively enhanced PGRN expression in the hippocampus of Tg2576 mice. This elevated PGRN expression significantly reduced amyloid plaque burden in these mice, accompanied by reductions in markers of inflammation and synaptic atrophy. The overexpression of PGRN was also found to increase activity of neprilysin, a key amyloid beta degrading enzyme. PGRN regulation of neprilysin activity could play a major role in the observed alterations in plaque burden. Thus, PGRN may be an effective therapeutic target for the treatment of AD.
颗粒蛋白前体（PGRN）是一种多功能蛋白质，在整个大脑中广泛表达，已被证明是中枢神经系统炎症的关键调节因子，还作为自分泌神经元生长因子发挥作用，对神经元的长期存活至关重要。PGRN已被证明可激活调节兴奋毒性、氧化应激、突触形成以及淀粉样蛋白生成的细胞信号通路。这些在中枢神经系统中的关键作用共同表明，PGRN有可能成为治疗各种神经退行性疾病，特别是阿尔茨海默病（AD）的重要治疗靶点。AD是痴呆症的主要病因，其特征是出现由淀粉样β蛋白（Aβ）聚集体组成的细胞外斑块，以及神经炎症、氧化应激、神经元丢失和突触萎缩。PGRN针对AD病理生理学多个关键特征的能力表明，增强其表达可能对这种疾病有益。在这里，我们描述了在AD转基因小鼠模型中使用慢病毒表达载体进行体内递送的PGRN基因转移的应用。PGRN基因的病毒载体递送有效地增强了Tg2576小鼠海马体中PGRN的表达。这种升高的PGRN表达显著降低了这些小鼠的淀粉样斑块负担，同时炎症和突触萎缩标志物也有所减少。还发现PGRN的过表达会增加脑啡肽酶的活性，脑啡肽酶是一种关键的淀粉样β降解酶。PGRN对脑啡肽酶活性的调节可能在观察到的斑块负担变化中起主要作用。因此，PGRN可能是治疗AD的有效治疗靶点。
