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Articles, Neurobiology of Disease

Calpain Activation in Alzheimer's Model Mice Is an Artifact of APP and Presenilin Overexpression

Takashi Saito, Yukio Matsuba, Naomi Yamazaki, Shoko Hashimoto and Takaomi C. Saido
Journal of Neuroscience 21 September 2016, 36 (38) 9933-9936; DOI: https://doi.org/10.1523/JNEUROSCI.1907-16.2016
Takashi Saito
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako 351-0198, Japan
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Yukio Matsuba
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako 351-0198, Japan
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Naomi Yamazaki
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako 351-0198, Japan
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Shoko Hashimoto
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako 351-0198, Japan
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Takaomi C. Saido
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako 351-0198, Japan
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Article Information

DOI 
https://doi.org/10.1523/JNEUROSCI.1907-16.2016
PubMed 
27656030
Published By 
Society for Neuroscience
History 
  • Received June 14, 2016
  • Revision received July 8, 2016
  • Accepted August 5, 2016
  • First published September 21, 2016.
  • Version of record published September 21, 2016.
Copyright & Usage 
Copyright © 2016 Saito et al. This article is freely available online through the J Neurosci Author Open Choice option.

Author Information

  1. Takashi Saito,
  2. Yukio Matsuba,
  3. Naomi Yamazaki,
  4. Shoko Hashimoto, and
  5. Takaomi C. Saido
  1. Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako 351-0198, Japan
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Author contributions

  1. Author contributions: T.S., S.H., and T.C.S. designed research; T.S., Y.M., N.Y., and T.C.S. performed research; T.S., Y.M., N.Y., and T.C.S. contributed unpublished reagents/analytic tools; T.S., Y.M., N.Y., and T.C.S. analyzed data; T.C.S. wrote the paper.

Disclosures

    • Received June 14, 2016.
    • Revision received July 8, 2016.
    • Accepted August 5, 2016.
  • This work was supported by a Grant-in-Aid for Scientific Research (B) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (T.S.); the Japan Science and Technology Agency Precursory Research for Embryonic Science and Technology (T.S.); and the Brain Mapping by Integrated Neurotechnologies for Disease Studies project of the Japan Agency for Medical Research and Development (T.C.S.). We thank Kazuhiro Yamakawa for providing antibodies to Nav1.1 and Charles Yokoyama for editing this manuscript.

  • T.S., Y.M., and T.C.S. serve as advisor, director, and CEO, respectively, for RIKEN BIO Co. Ltd., a RIKEN venture based at the Brain Science Institute, Central Building, Wako, Japan.

  • This is an Open Access article distributed under the terms of the Creative Commons Attribution License Creative Commons Attribution 4.0 International, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

  • Correspondence should be addressed to Takaomi C. Saido at the above address. saido{at}brain.riken.jp

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The Journal of Neuroscience: 36 (38)
Journal of Neuroscience
Vol. 36, Issue 38
21 Sep 2016
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Calpain Activation in Alzheimer's Model Mice Is an Artifact of APP and Presenilin Overexpression
Takashi Saito, Yukio Matsuba, Naomi Yamazaki, Shoko Hashimoto, Takaomi C. Saido
Journal of Neuroscience 21 September 2016, 36 (38) 9933-9936; DOI: 10.1523/JNEUROSCI.1907-16.2016

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Calpain Activation in Alzheimer's Model Mice Is an Artifact of APP and Presenilin Overexpression
Takashi Saito, Yukio Matsuba, Naomi Yamazaki, Shoko Hashimoto, Takaomi C. Saido
Journal of Neuroscience 21 September 2016, 36 (38) 9933-9936; DOI: 10.1523/JNEUROSCI.1907-16.2016
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Keywords

  • amyloid
  • calpain
  • Nav1.1
  • p25

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  • Calpain activation in Alzheimer's disease: Comments on Saito et al.
    Li-Huei Tsai
    Published on: 26 September 2016
  • Published on: (26 September 2016)
    Page navigation anchor for Calpain activation in Alzheimer's disease: Comments on Saito et al.
    Calpain activation in Alzheimer's disease: Comments on Saito et al.
    • Li-Huei Tsai, Professor
    • Other Contributors:
      • Ralph A. Nixon

    Saito and colleagues stated that 60% of the phenotypes observed in traditional AD mouse models are merely "artifact", based on the absence of these phenotypes in their APP knock-in mouse models carrying two or three distinct APP mutations (Saito et al., 2014). In this line, they claimed that calpain activation, p25 production and Nav1.1 reduction are all artifacts of APP and PS1 overexpression. Careful examination of the lim...

    Show More

    Saito and colleagues stated that 60% of the phenotypes observed in traditional AD mouse models are merely "artifact", based on the absence of these phenotypes in their APP knock-in mouse models carrying two or three distinct APP mutations (Saito et al., 2014). In this line, they claimed that calpain activation, p25 production and Nav1.1 reduction are all artifacts of APP and PS1 overexpression. Careful examination of the limited data presented, however, shows that this conclusion is not strongly supported. The data suffer from absence of some controls and insufficient analysis. Specific points that should be considered are highlighted below:

    1. APP duplication is known to cause familial Alzheimer's disease. Similarly, individuals with Down's syndrome caused by trisomy of chromosome 21 (which contains the APP gene) also develop early-onset Alzheimer's disease. Moreover, there is evidence that individual neurons in sporadic AD patients show differences in APP gene copy number (Bushman et al., 2015). Therefore, given that APP duplication (and its overexpression) is a cause of Alzheimer's disease, it is misleading to characterize the increased calpain activity as an artifact of APP overexpression.

    2. The authors suggest that the differences they observe between their APP mutant knock-in model and other transgenic models are simply due to the presence or absence of APP overexpression. This is a very limited interpretation. It is well established that AD-related pathogenic phenotypes in mouse models not only relate to APP expression and total Abeta generation, but also to Abeta oligomer formation and localization, both neuroanatomic and subcellular. These important factors have not been analyzed in this paper or the preceding report (Saito et al., 2014).

    3. Increased calpain activity and marked reduction of calpastatin (Cast) have not only been shown in mouse models of Alzheimer's disease, but have also been widely reported in post-mortem brain samples of Alzheimer's disease patients (for instance, Saito et al., 1993; Rao et al., 2008; Laske et al., 2015; Kurbatskava et al., 2016). Thus, the lack of increased calpain activity in the mouse model used by Saito and colleagues calls into question the physiological relevance of their model, and whether the APP23 and other transgenic models are closer approximations of the human disease.

    4. Increased p25 generation in Cast-KO mice under pathological conditions has been shown previously (Sato et al., 2011). However, in Fig. 1, Cast-KO/APPNL-F/NL-F mice do not show increased p25 signal, which should occur if as expected, it reflects calpain-dependent p35 cleavage. This raises the question of specificity and whether the authors are in fact measuring p25. The authors extensively discuss crosses with a Cast-KO mouse, but they do not show any p25 data from Cast-KO mouse brain or APP23 crossed to Cast-KO. These blots should show elevated p25 signal and would serve as positive controls.

    5. The knock-in APPNL-F/NL-F mice were examined only at 2 years of age. It is possible that calpain activity is downregulated by this late age. It is also possible that calpain gene(s) are disrupted in their model. These possibilities may explain why the cross of APPNL-F/NL-F with Cast-KO did not increase p25 generation. Moreover, examination of the gel in Fig. 1 suggests that p35 may be elevated in APPNL-F/NL-F compared with the other genotypes, consistent with calpain downregulation. These control experiments should be conducted before making conclusions. To rigorously assess p25 generation, a broader range of ages should also be analyzed.

    A similar concern applies to Fig 2, in which conclusions about sodium channel expression are based solely on a 2-year-old brain sample, and is generalized to suggest that a previous report of sodium channel downregulation in the J20 model was unique to that model. Furthermore, the present paper utilizes Western blotting of whole brain homogenates, a highly insensitive approach for assessing sodium channel regulation in specific interneuron subpopulations. In particular, there is no in situ analysis by immunofluorescence, electrophysiology or other methods.

    6. The authors state that calpain-mediated p25 generation is an artifact caused by membrane protein overexpression such as APP or PS1, but they never address this directly. There are multiple studies demonstrating that in the absence of APP overexpression, organotypic hippocampal slices, cultured primary neurons, and even primary microglia exposed to Abeta show increased p25 generation (for instance, Zheng et al., 2005; Ma et al., 2013; Seo et al., 2014). Moreover, PS1 mutations were shown indisputably to disrupt calcium homeostasis and activate calcium-dependent enzymes (Morgan et al., 2007; Muller et al., 2011), which can increase calpain activity and subsequent p25 generation. Extending claims of artifact to PS1-related mouse models when their analysis is limited to APP models is scientifically unwarranted.

    7. Finally, there is a large body of literature from many mouse models of neurological disorders that shows p25 production that is unrelated to overexpression of membrane proteins. These include models of tauopathies (Rao et al., 2014), ischemia (Meyer et al., 2014), and Parkinson's disease (Smith et al., 2006). Saito et al (2016) did not cite any of these studies. Furthermore, the statement that "overexpression of a mutant tau protein, a cytosolic protein, exhibited no effect on p25 levels (data not shown)" directly contradicts previous literature, a discrepancy that was not discussed. Based on points 6 and 7, it is misleading to characterize the p25 generation as an artifact of membrane protein overexpression.

    References

    Bushman DM, Kaeser GE, Siddoway B, Westra JW, Rivera RR, Rehen SK, Yung YC, Chun J. Genomic mosaicism with increased amyloid precursor protein (APP) gene copy number in single neurons from sporadic Alzheimer's disease brains. Elife 2015 doi: 10.7554/eLife.05116

    Kurbatskaya K, Philips EC, Croft CL, Dentoni G, Hughes MM, Wade MA, Al-Sarraj S, Troakes C, O'Neill MJ, Perez-Nievas BG, Hanger DP, Nobel W. Upregulation of calpain activity precedes tau phosphorylation and loss of synaptic proteins in Alzheimer's disease brain. Acta Neuropathol Commun 2016 4:34.

    Laske C, Stellos K, Kempter I, Stransky E, Maetzler W, Fleming I, Randriamboavonjy V. Increased cerebrospinal fluid calpain activity and microparticle levels in Alzheimer's disease. Alzheimers Dement 2015 11(5):465-74.

    Ma Y, Bao J, Zhao X, Shen H, Lv J, Ma S, Zhang X, Li Z, Wang S, Wang Q, Ji J. Activated cyclin-dependent kinase 5 promotes microglial phagocytosis of fibrillar beta-amyloid by up-regulating lipoprotein lipase expression. Mol Cell Proteomics 2013 12(10):2833-44.

    Meyer DA, Torres-Altoro Ml, Tan Z, Tozzi A, Di Filippo M, DiNapoli V, Plattner F, Kansy JW, Benkovic SA, Huber JD, Miller DB, Greengard P, Calabresi P, Rosen CL, Bibb JA. Ischemic stroke injury is mediated by aberrant Cdk5. J Neurosci 2014 34(24):8259-67.

    Morgan GA, Guo Q, Chan SL, Gary DS, Osborne BA, Mattson MP. Defects of immune regulation in the presenilin-1 mutant knockin mouse. Neuromolecular Med 2007 9(1):35-45.

    Muller M, Cardenas C, Mei L, Cheung KH, Foskett JK. Constitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (InsP3R) Ca2+ signaling. Proc Natl Acad Sci U S A 2011 109(32):13293-8.

    Rao MV, Mohan PS, Peterhoff CM, Yang DS, Schmidt SD, Stavrides PH, Campbell J, Chen Y, Jiang Y, Paskevich PA, Cataldo AM, Haroutunian V, Nixon RA. Marked calpastatin (CAST) depletion in Alzheimer's disease accelerates cytoskeleton disruption and neurodegeneration: neuroprotection by CAST overexpression. J Neurosci 2008 28(47):12241-54.

    Rao MV, McBrayer MK, Campbell J, Kumar A, Hashim A, Sershen H, Stavrides PH, Ohno M, Hutton M, Nixon RA. Specific calpain inhibition by calpastatin prevents tauopathy and neurodegeneration and restores normal lifespan in tau P301L mice. J Neurosci 2014 34(28):9222-34.

    Saito K, Elce JS, Hamos JE, Nixon RA. Widespread activation of calcium-activated neutral proteinase (calpain) in the brain in Alzheimer disease: a potential molecular basis for neuronal degeneration. Proc Natl Acad Sci U S A 1993 90(7):2628-32.

    Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, Iwata N, Saido TC. Single App knock-in mouse models of Alzheimer's disease. Nat Neurosci 2014 17(5):661-3.

    Sato K, Minegishi S, Takano J, Plattner F, Saito T, Asada A, Kawahara H, Iwata N, Saido TC, Hisanaga S. Calpastatin, an endogenous calpain- inhibitor protein, regulates the cleavage of the Cdk5 activator p35 to p25. J Neurochem 2011 117(3):504-15.

    Seo J, Giusti-Rodriguez P, Zhou Y, Rudenko A, Cho S, Ota KT, Park C, Patzke H, Madabhushi R, Pan L, Mungenast AE, Guan JS, Delalle I, Tsai LH. Activity-dependent p25 generation regulates synaptic plasticity and Abeta- induced cognitive impairment. Cell 2014 157(2):486-98.

    Smith PD, Mount MP, Shree R, Callaghan S, Slack RS, Anisman H, Vincent I, Wang X, Mao Z, Park DS. Calpain-regulated p35/Cdk5 plays a central role in dopaminergic neuron death through modulation of the transcription factor myocyte enhancer factor 2. J Neurosci 2006 26(2):440-7.

    Zheng YL, Kesavapany S, Gravell M, Hamilton RS, Schubert M, Amin N, Albers W, Grant P, Pant HC. A Cdk5 inhibitory peptide reduces tau hyperphosphorylation and apoptosis in neurons. EMBO J 2005 24(1):209-20.

    Conflict of Interest:

    None declared

    Show Less
    Competing Interests: None declared.

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