Progranulin haploinsufficiency reduces amyloid beta deposition in Alzheimer's disease model mice

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Author(s)

    • HOSOKAWA Masato Hosokawa 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
    • TANAKA Yoshinori Tanaka Yoshinori
    • 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
    • ARAI Tetsuaki Arai Tetsuaki
    • 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
    • KONDO Hiromi Kondo Hiromi
    • Histology center, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan
    • AKIYAMA Haruhiko Akiyama Haruhiko
    • 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
    • HASEGAWA Masato 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

Abstract

<p>Granulin (<i>Grn</i>) mutations were identified in familial frontotemporal lobar degeneration (FTLD) patients with TAR DNA-binding protein of 43 kd (TDP-43) pathology. <i>Grn</i> 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 <i>Grn</i> 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 <i>Grn</i>-deficient mice, producing APP transgenic mice harboring the <i>Grn</i> hemizygote (APP/<i>Grn<sup>+/−</sup></i>). Brains were collected from 16–18-month-old APP and APP/<i>Grn<sup>+/−</sup></i> 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/<i>Grn<sup>+/−</sup></i> mice as compared to APP mice. Immunoblotting analysis revealed that Aβ was reduced in the sarkosyl-insoluble fraction of 16–18-month-old APP/<i>Grn<sup>+/−</sup></i> mice as compared with that of APP transgenic mice. Our data suggest that PGRN haploinsufficiency may decrease accumulation of Aβ.</p>

Journal

  • Experimental Animals

    Experimental Animals 67(1), 63-70, 2018

    Japanese Association for Laboratory Animal Science

Codes

  • NII Article ID (NAID)
    130006339997
  • NII NACSIS-CAT ID (NCID)
    AA11032321
  • Text Lang
    ENG
  • ISSN
    1341-1357
  • NDL Article ID
    028779151
  • NDL Call No.
    Z54-H752
  • Data Source
    NDL  J-STAGE 
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