Hosokawa Masato, Tanaka Yoshinori, Arai Tetsuaki, Kondo Hiromi, Akiyama Haruhiko, Hasegawa Masato
Dementia research project, Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
Department of Neuropsychiatry, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8576 Japan.
Exp Anim. 2018 Feb 9;67(1):63-70. doi: 10.1538/expanim.17-0060. Epub 2017 Aug 25.
Granulin (Grn) mutations were identified in familial frontotemporal lobar degeneration (FTLD) patients with TAR DNA-binding protein of 43 kd (TDP-43) pathology. Grn transcript haploinsufficiency is proposed as a disease mechanism that leads to the loss of functional progranulin (PGRN) protein. Thus, these mutations are strongly involved in FTLD pathogenesis. Moreover, recent findings indicate that Grn mutations are associated with other neurodegenerative disorders with tau pathology, including Alzheimer's disease. To investigate the influence of PGRN on amyloid beta (Aβ) accumulation, amyloid precursor protein (APP) transgenic mice were interbred with Grn-deficient mice, producing APP transgenic mice harboring the Grn hemizygote (APP/Grn). Brains were collected from 16-18-month-old APP and APP/Grn mice and sequential extraction of proteins, immunoblotting and immunohistochemical analysis were performed. Immunohistochemical analysis showed that the number and area of Aβ plaque was significantly decreased in APP/Grn mice as compared to APP mice. Immunoblotting analysis revealed that Aβ was reduced in the sarkosyl-insoluble fraction of 16-18-month-old APP/Grn mice as compared with that of APP transgenic mice. Our data suggest that PGRN haploinsufficiency may decrease accumulation of Aβ.
在患有43kd的TAR DNA结合蛋白（TDP - 43）病理改变的家族性额颞叶痴呆（FTLD）患者中发现了颗粒蛋白（Grn）突变。Grn转录本单倍剂量不足被认为是一种导致功能性前颗粒蛋白（PGRN）丢失的疾病机制。因此，这些突变与FTLD的发病机制密切相关。此外，最近的研究结果表明，Grn突变与其他伴有tau病理改变的神经退行性疾病有关，包括阿尔茨海默病。为了研究PGRN对淀粉样β蛋白（Aβ）积累的影响，将淀粉样前体蛋白（APP）转基因小鼠与Grn基因缺陷小鼠杂交，培育出携带Grn半合子的APP转基因小鼠（APP/Grn）。收集16 - 18月龄的APP小鼠和APP/Grn小鼠的大脑，进行蛋白质的连续提取、免疫印迹和免疫组化分析。免疫组化分析显示，与APP小鼠相比，APP/Grn小鼠中Aβ斑块的数量和面积显著减少。免疫印迹分析表明，与APP转基因小鼠相比，16 - 18月龄APP/Grn小鼠的 Sarkosyl不溶性部分中的Aβ减少。我们的数据表明，PGRN单倍剂量不足可能会减少Aβ的积累。
