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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.·2018·Journal of Biological Chemistry
DOI 10.1074/jbc.m117.811315
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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 by AD pathology 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 of Aβ pathology. Thorough examinations indicated that no ER stress responses arose in App-KI or single APP-Tg mice. These results suggest that PS1 overexpression 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…

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Figure 2 Expression of ER stress markers in P301S-Tau-Tg mice. a , expression levels of ER stress markers in the cortices (3-15 months ( M )) and hippocampi (12 months) of WT and P301S-Tau-Tg mice were determined. Arrowheads show bands of CHOP and p-eIF2 𝛂 , and asterisks show nonspecific bands. b , XBP1 mRNAwas detected by semiquantitative reverse transcription-PCR. c and d , mean levels ± S.E. of relative expression of ER stress markers ( n = 3). c , cortex; d , hippocampus. Differences between groups were examined for statistical significance via two-way ANOVA. n.s. , no significant difference. Error bars represent S.E.
Figure 2 Expression of ER stress markers in P301S-Tau-Tg mice. a , expression levels of ER stress markers in the cortices (3-15 months ( M )) and hippocampi (12 months) of WT and P301S-Tau-Tg mice were determined. Arrowheads show bands of CHOP and p-eIF2 𝛂 , and asterisks show nonspecific bands. b , XBP1 mRNAwas detected by semiquantitative reverse transcription-PCR. c and d , mean levels ± S.E. of relative expression of ER stress markers ( n = 3). c , cortex; d , hippocampus. Differences between groups were examined for statistical significance via two-way ANOVA. n.s. , no significant difference. Error bars represent S.E.From the PDF

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Metadata

Authors
Hashimoto, S., Ishii, A., Kamano, N., Watamura, N., Saito, T., Ohshima, T., Yokosuka, M., & Saido, T. C.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2018-03
Volume
293
Issue
9
Pages
3118-3125
ISSN
0021-9258
DOI
10.1074/jbc.m117.811315
Cited by
76
References
8
Language
en
Licence
Funders
  • Ministry of Education, Culture, Sports, Science and Technology (Grant-in-aid for young scientists (B) 15K19036, Grant-in-aid for scientific research (B) 26290019)
  • Japan Agency for Medical Research and Development (JP15km0908001)

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CoChat. (2026). Citation check: Endoplasmic reticulum stress responses in mouse models of Alzheimer's disease: Overexpression paradigm versus knockin paradigm. https://app.cochat.ai/papers/10.1074/jbc.m117.811315
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Hashimoto, S., Ishii, A., Kamano, N., Watamura, N., Saito, T., Ohshima, T., Yokosuka, M., & Saido, T. C. (2018). Endoplasmic reticulum stress responses in mouse models of Alzheimer's disease: Overexpression paradigm versus knockin paradigm. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m117.811315

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