Endoplasmic reticulum stress responses in mouse models of Alzheimer's disease: Overexpression paradigm versus knockin paradigm

Shoko Hashimoto, Ayano Ishii, Naoko Kamano, Naoto Watamura, Takashi Saito, Toshio Ohshima, Makoto Yokosuka, Takaomi C. Saido

    Research output: Contribution to journalArticle

    16 Citations (Scopus)

    Abstract

    Endoplasmic reticulum (ER) stress is believed to play an important role in the etiology of Alzheimer's disease (AD). The accumulation of misfolded proteins and perturbation of intracellular calcium homeostasis are thought to underlie the induction of ER stress, resulting in neuronal dysfunction and cell death. Several reports have shown an increased ER stress response in amyloid precursor protein (APP) and presenilin1 (PS1) double-transgenic (Tg) AD mouse models. However, whether the ER stress observed in these mouse models is actually caused byADpathology remains unclear. APP and PS1 contain one and nine transmembrane domains, respectively, for which it has been postulated that overexpressed membrane proteins can become wedged in a misfolded configuration in ER membranes, thereby inducing nonspecific ER stress. Here, we used an App-knockin (KI) AD mouse model that accumulates amyloid-β (Aβ) peptide without overexpressing APP to investigate whether the ER stress response is heightened because ofAβ pathology. Thorough examinations indicated that no ER stress responses arose in App-KI or single APP-Tg mice. These results suggest thatPS1overexpression or mutation induced a nonspecific ER stress response that was independent of Aβ pathology in the double-Tg mice. Moreover, we observed no ER stress in a mouse model of tauopathy (P301S-Tau-Tg mice) at various ages, suggesting that ER stress is also not essential in tau pathology-induced neurodegeneration. We conclude that the role of ER stress in AD pathogenesis needs to be carefully addressed in future studies.

    Original languageEnglish
    Pages (from-to)3118-3125
    Number of pages8
    JournalJournal of Biological Chemistry
    Volume293
    Issue number9
    DOIs
    Publication statusPublished - 2018 Jan 1

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    Endoplasmic Reticulum Stress
    Alzheimer Disease
    Amyloid beta-Protein Precursor
    Pathology
    Application programs
    Transgenic Mice
    Cell death
    Amyloid
    Tauopathies
    Membrane Proteins
    Calcium
    Membranes
    Peptides
    Endoplasmic Reticulum
    Homeostasis
    Cell Death

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

    Cite this

    Endoplasmic reticulum stress responses in mouse models of Alzheimer's disease : Overexpression paradigm versus knockin paradigm. / Hashimoto, Shoko; Ishii, Ayano; Kamano, Naoko; Watamura, Naoto; Saito, Takashi; Ohshima, Toshio; Yokosuka, Makoto; Saido, Takaomi C.

    In: Journal of Biological Chemistry, Vol. 293, No. 9, 01.01.2018, p. 3118-3125.

    Research output: Contribution to journalArticle

    Hashimoto, Shoko ; Ishii, Ayano ; Kamano, Naoko ; Watamura, Naoto ; Saito, Takashi ; Ohshima, Toshio ; Yokosuka, Makoto ; Saido, Takaomi C. / Endoplasmic reticulum stress responses in mouse models of Alzheimer's disease : Overexpression paradigm versus knockin paradigm. In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 9. pp. 3118-3125.
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