Minami S Sakura, Min Sang-Won, Krabbe Grietje, Wang Chao, Zhou Yungui, Asgarov Rustam, Li Yaqiao, Martens Lauren H, Elia Lisa P, Ward Michael E, Mucke Lennart, Farese Robert V, Gan Li
1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
Gladstone Institute of Neurological Disease, San Francisco, California, USA.
Nat Med. 2014 Oct;20(10):1157-64. doi: 10.1038/nm.3672. Epub 2014 Sep 28.
Haploinsufficiency of the progranulin (PGRN) gene (GRN) causes familial frontotemporal lobar degeneration (FTLD) and modulates an innate immune response in humans and in mouse models. GRN polymorphism may be linked to late-onset Alzheimer's disease (AD). However, the role of PGRN in AD pathogenesis is unknown. Here we show that PGRN inhibits amyloid β (Aβ) deposition. Selectively reducing microglial expression of PGRN in AD mouse models impaired phagocytosis, increased plaque load threefold and exacerbated cognitive deficits. Lentivirus-mediated PGRN overexpression lowered plaque load in AD mice with aggressive amyloid plaque pathology. Aβ plaque load correlated negatively with levels of hippocampal PGRN, showing the dose-dependent inhibitory effects of PGRN on plaque deposition. PGRN also protected against Aβ toxicity. Lentivirus-mediated PGRN overexpression prevented spatial memory deficits and hippocampal neuronal loss in AD mice. The protective effects of PGRN against Aβ deposition and toxicity have important therapeutic implications. We propose enhancing PGRN as a potential treatment for PGRN-deficient FTLD and AD.
前颗粒蛋白（PGRN）基因（GRN）单倍剂量不足会导致家族性额颞叶痴呆（FTLD），并在人类和小鼠模型中调节先天性免疫反应。GRN基因多态性可能与晚发性阿尔茨海默病（AD）有关。然而，PGRN在AD发病机制中的作用尚不清楚。在此我们表明，PGRN可抑制淀粉样β蛋白（Aβ）沉积。在AD小鼠模型中选择性降低小胶质细胞中PGRN的表达会损害吞噬作用，使斑块负荷增加三倍，并加剧认知缺陷。慢病毒介导的PGRN过表达降低了具有侵袭性淀粉样斑块病理特征的AD小鼠的斑块负荷。Aβ斑块负荷与海马PGRN水平呈负相关，表明PGRN对斑块沉积具有剂量依赖性抑制作用。PGRN还可抵御Aβ毒性。慢病毒介导的PGRN过表达可预防AD小鼠的空间记忆缺陷和海马神经元丢失。PGRN对Aβ沉积和毒性的保护作用具有重要的治疗意义。我们建议增强PGRN水平作为治疗PGRN缺乏型FTLD和AD 的潜在疗法。
