Thygesen Camilla, Ilkjær Laura, Kempf Stefan J, Hemdrup Anne Louise, von Linstow Christian Ulrich, Babcock Alicia A, Darvesh Sultan, Larsen Martin R, Finsen Bente
Department of Neurobiology, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
Front Cell Neurosci. 2018 Nov 6;12:397. doi: 10.3389/fncel.2018.00397. eCollection 2018.
Neuroinflammation, characterized by chronic activation of the myeloid-derived microglia, is a hallmark of Alzheimer's disease (AD). Systemic inflammation, typically resulting from infection, has been linked to the progression of AD due to exacerbation of the chronic microglial reaction. However, the mechanism and the consequences of this exacerbation are largely unknown. Here, we mimicked systemic inflammation in AD with weekly intraperitoneal (i.p.) injections of APP/PS1 transgenic mice with lipopolysaccharide (LPS) from 9 to 12 months of age, corresponding to the period with the steepest increase in amyloid pathology. We found that the repeated LPS injections ameliorated amyloid pathology in the neocortex while increasing the neuroinflammatory reaction. To elucidate mechanisms, we analyzed the proteome of the hippocampus from the same mice as well as in unique samples of CNS myeloid cells. The repeated LPS injections stimulated protein pathways of the complement system, retinoid receptor activation and oxidative stress. CNS myeloid cells from transgenic mice showed enrichment in pathways of amyloid-beta clearance and elevated levels of the lysosomal protease cathepsin Z, as well as amyloid precursor protein, apolipoprotein E and clusterin. These proteins were found elevated in the proteome of both LPS and vehicle injected transgenics, and co-localized to CD11b microglia in transgenic mice and in primary murine microglia. Additionally, cathepsin Z, amyloid precursor protein, and apolipoprotein E appeared associated with amyloid plaques in neocortex of AD cases. Interestingly, cathepsin Z was expressed in microglial-like cells and co-localized to CD68 microglial lysosomes in AD cases, and it was expressed in perivascular cells in AD and control cases. Taken together, our results implicate systemic LPS administration in ameliorating amyloid pathology in early-to-mid stage disease in the APP/PS1 mouse and attract attention to the potential disease involvement of cathepsin Z expressed in CNS myeloid cells in AD.
神经炎症，其特征为骨髓来源的小胶质细胞慢性激活，是阿尔茨海默病（AD）的一个标志。全身性炎症通常由感染引起，由于慢性小胶质细胞反应加剧，已被证明与AD的进展有关。然而，这种加剧的机制和后果在很大程度上尚不清楚。在此，我们通过每周腹腔内（i.p.）注射脂多糖（LPS）来模拟AD中的全身性炎症，对9至12月龄的APP/PS1转基因小鼠进行注射，这一时期对应淀粉样病理变化增长最迅速的阶段。我们发现，重复注射LPS可改善新皮质中的淀粉样病理变化，同时增加神经炎症反应。为阐明机制，我们分析了来自同一批小鼠海马体的蛋白质组以及中枢神经系统髓样细胞的独特样本。重复注射LPS刺激了补体系统、视黄酸受体激活和氧化应激的蛋白质通路。转基因小鼠的中枢神经系统髓样细胞显示出淀粉样β清除途径的富集，以及溶酶体蛋白酶组织蛋白酶Z、淀粉样前体蛋白、载脂蛋白E和簇集蛋白水平的升高。在注射LPS和注射赋形剂的转基因小鼠的蛋白质组中均发现这些蛋白质水平升高，并且在转基因小鼠和原代小鼠小胶质细胞中与CD11b小胶质细胞共定位。此外，在AD病例的新皮质中，组织蛋白酶Z、淀粉样前体蛋白和载脂蛋白E似乎与淀粉样斑块相关。有趣的是，组织蛋白酶Z在AD病例中在小胶质细胞样细胞中表达，并与CD68小胶质溶酶体共定位，并且在AD和对照病例的血管周围细胞中也有表达。综上所述，我们的结果表明全身性给予LPS可改善APP/PS1小鼠早期至中期疾病中的淀粉样病理变化，并引起人们对AD中枢神经系统髓样细胞中表达的组织蛋白酶Z潜在疾病参与的关注。
