Department of Neurology and The Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA.
Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA.
J Alzheimers Dis. 2017;60(3):1143-1160. doi: 10.3233/JAD-170634.
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the presence of intracellular neurofibrillary tangles (NFTs) containing hyperphosphorylated tau, and the extracellular deposition of amyloid plaques (APs) with misfolded amyloid-β (Aβ) peptide. Glia maturation factor (GMF), a highly conserved pro-inflammatory protein, isolated and cloned in our laboratory, has been shown to activate glial cells leading to neuroinflammation and neurodegeneration in AD. We hypothesized that inflammatory reactions promoted by NLRP3-Caspase-1inflammasome pathway trigger dysfunction in autophagy and accumulation of Aβ which is amplified and regulated by GMF in AD. In this study, using immunohistochemical techniques we analyzed components of the NLRP3 inflammasome and autophagy- lysosomal markers in relation to Aβ, p-tau and GMF in human postmortem AD and age-matched non-AD brains. Tissue sections were prepared from the temporal cortex of human postmortem brains. Here, we demonstrate an increased expression of the inflammasome components NLRP3 and Caspase-1 and the products of inflammasome activation IL-1β and IL-18 along with GMF in the temporal cortex of AD brains. These inflammasome components and the pro-inflammatory cytokines co-localized with GMF in the vicinity and periphery of the APs and NFTs. Moreover, using double immunofluorescence staining, AD brain displayed an increase in the autophagy SQSTM1/p62 and LC3 positive vesicles and the lysosomal marker LAMP1 that also co-localized with GMF, Aβ and hyperphosphorylated p-tau. Our results indicate that in AD, the neuroinflammation promoted by the NLRP3 inflammasome may be amplified and regulated by GMF, which further impairs clearance of protein aggregates mediated by the auto-phagosomal pathway.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征是存在含有过度磷酸化 tau 的细胞内神经原纤维缠结（NFTs），以及含有错误折叠淀粉样-β（Aβ）肽的细胞外淀粉样斑块（APs）沉积。胶质细胞成熟因子（GMF）是一种高度保守的促炎蛋白，我们实验室分离并克隆了该蛋白，它已被证明可激活神经胶质细胞，导致 AD 中的神经炎症和神经退行性变。我们假设，NLRP3-Caspase-1 炎性小体途径引发的炎症反应会触发自噬功能障碍和 Aβ的积累，而 GMF 会放大和调节 AD 中的 Aβ的积累。在这项研究中，我们使用免疫组织化学技术分析了 NLRP3 炎性小体和自噬溶酶体标志物的成分与 AD 和年龄匹配的非 AD 大脑中的 Aβ、p-tau 和 GMF 的关系。组织切片取自人类死后大脑的颞叶皮层。在这里，我们证明了在 AD 大脑的颞叶皮层中，炎性小体成分 NLRP3 和 Caspase-1 及其激活产物 IL-1β 和 IL-18 以及 GMF 的表达增加。这些炎性小体成分和促炎细胞因子与 AP 和 NFT 附近和周围的 GMF 共定位。此外，通过双免疫荧光染色，AD 大脑显示自噬 SQSTM1/p62 和 LC3 阳性囊泡和溶酶体标志物 LAMP1 的增加，这些标志物也与 GMF、Aβ 和过度磷酸化的 p-tau 共定位。我们的结果表明，在 AD 中，NLRP3 炎性小体促进的神经炎症可能被 GMF 放大和调节，这进一步损害了自噬体途径介导的蛋白质聚集体的清除。
