Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

DISC1 regulates trafficking and processing of APP and Aβ generation

Molecular Psychiatry volume 20, pages 874–879 (2015)Cite this article

Subjects

Abstract

We report the novel regulation of proteolytic processing of amyloid precursor protein (APP) by DISC1, a major risk factor for psychiatric illnesses, such as depression and schizophrenia. RNAi knockdown of DISC1 in mature primary cortical neurons led to a significant increase in the levels of intracellular α-C-terminal fragment of APP (APP-CTFα) and the corresponding N-terminal-secreted ectodomain product sAPPα. DISC1 knockdown also elicited a significant decrease in the levels of amyloid beta (Aβ)42 and Aβ40. These aberrant proteolytic events were successfully rescued by co-expression of wild-type DISC1, but not by mutant DISC1 lacking the amino acids required for the interaction with APP, suggesting that APP–DISC1 protein interactions are crucial for the regulation of the C-terminal proteolysis. In a genetically engineered model in which a major full-length DISC1 isoform is depleted, consistent changes in APP processing were seen: an increase in APP-CTFα and decrease in Aβ42 and Aβ40 levels. Finally, we found that knockdown of DISC1 increased the expression of APP at the cell surface and decreased its internalization. The presented DISC1 mechanism of APP proteolytic processing and Aβ peptide generation, which is central to Alzheimer’s disease pathology, suggests a novel interface between neurological and psychiatric conditions.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Masters CL, Selkoe DJ . Biochemistry of Amyloid beta-Protein and Amyloid Deposits in Alzheimer Disease. Cold Spring Harb Perspect Med 2012; 2: a006262.

  2. Haass C, Kaether C, Thinakaran G, Sisodia S . Trafficking and Proteolytic Processing of APP. Cold Spring Harb Perspect Med 2012; 2: a006270.

  3. Cruts M Alzheimer’s disease mutation database, 2012. Available from http://www.molgen.ua.ac.be/ADMutations.

  4. Jones CT, Morris S, Yates CM, Moffoot A, Sharpe C, Brock DJ et al. Mutation in codon 713 of the beta amyloid precursor protein gene presenting with schizophrenia. Nat Genet 1992; 1: 306–309.

    Article  CAS  Google Scholar 

  5. Mucke L, Selkoe DJ . Neurotoxicity of Amyloid beta-Protein: synaptic and Network Dysfunction. Cold Spring Harb Perspect Med 2012; 2: a006338.

    Article  Google Scholar 

  6. Westmark CJ . What's hAPPening at synapses? The role of amyloid beta-protein precursor and beta-amyloid in neurological disorders. Mol Psychiatry 2013; 18: 425–434.

    Article  CAS  Google Scholar 

  7. Brandon NJ, Sawa A . Linking neurodevelopmental and synaptic theories of mental illness through DISC1. Nat Rev Neurosci 2011; 12: 707–722.

    Article  CAS  Google Scholar 

  8. Porteous DJ, Millar JK, Brandon NJ, Sawa A . DISC1 at 10: connecting psychiatric genetics and neuroscience. Trends Mol Med 2011; 17: 699–706.

    Article  CAS  Google Scholar 

  9. Young-Pearse TL, Suth S, Luth ES, Sawa A, Selkoe DJ . Biochemical and functional interaction of disrupted-in-schizophrenia 1 and amyloid precursor protein regulates neuronal migration during mammalian cortical development. J Neurosci 2010; 30: 10431–10440.

    Article  CAS  Google Scholar 

  10. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R et al. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 2003; 39: 409–421.

    Article  CAS  Google Scholar 

  11. Hara MR, Agrawal N, Kim SF, Cascio MB, Fujimuro M, Ozeki Y et al. S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nat Cell Biol 2005; 7: 665–674.

    Article  CAS  Google Scholar 

  12. Kamiya A, Kubo K, Tomoda T, Takaki M, Youn R, Ozeki Y et al. A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol 2005; 7: 1167–1178.

    Article  Google Scholar 

  13. Seshadri S, Kamiya A, Yokota Y, Prikulis I, Kano S, Hayashi-Takagi A et al. Disrupted-in-Schizophrenia-1 expression is regulated by beta-site amyloid precursor protein cleaving enzyme-1-neuregulin cascade. Proc Natl Acad Sci USA 2010; 107: 5622–5627.

    Article  CAS  Google Scholar 

  14. Lois C, Hong EJ, Pease S, Brown EJ, Baltimore D . Germline transmission and tissue-specific expression of transgenes delivered by lentiviral vectors. Science 2002; 295: 868–872.

    Article  CAS  Google Scholar 

  15. Ishizuka K, Chen J, Taya S, Li W, Millar JK, Xu Y et al. Evidence that many of the DISC1 isoforms in C57BL/6J mice are also expressed in 129S6/SvEv mice. Mol Psychiatry 2007; 12: 897–899.

    Article  CAS  Google Scholar 

  16. Kuroda K, Yamada S, Tanaka M, Iizuka M, Yano H, Mori D et al. Behavioral alterations associated with targeted disruption of exons 2 and 3 of the Disc1 gene in the mouse. Hum Mol Genet 2011; 20: 4666–4683.

    Article  CAS  Google Scholar 

  17. Schmidt SD, Jiang Y, Nixon RA, Mathews PM . Tissue processing prior to protein analysis and amyloid-beta quantitation. Methods Mol Biol 2005; 299: 267–278.

    CAS  PubMed  Google Scholar 

  18. Schmidt SD, Nixon RA, Mathews PM . ELISA method for measurement of amyloid-beta levels. Methods Mol Biol 2005; 299: 279–297.

    CAS  PubMed  Google Scholar 

  19. Chyung JH, Selkoe DJ . Inhibition of receptor-mediated endocytosis demonstrates generation of amyloid beta-protein at the cell surface. J Biol Chem 2003; 278: 51035–51043.

    Article  CAS  Google Scholar 

  20. Parisiadou L, Efthimiopoulos S . Expression of mDab1 promotes the stability and processing of amyloid precursor protein and this effect is counteracted by X11alpha. Neurobiol Aging 2007; 28: 377–388.

    Article  CAS  Google Scholar 

  21. Hoe HS, Lee KJ, Carney RS, Lee J, Markova A, Lee JY et al. Interaction of reelin with amyloid precursor protein promotes neurite outgrowth. J Neurosci 2009; 29: 7459–7473.

    Article  CAS  Google Scholar 

  22. Jorissen E, Prox J, Bernreuther C, Weber S, Schwanbeck R, Serneels L et al. The disintegrin/metalloproteinase ADAM10 is essential for the establishment of the brain cortex. J Neurosci 2010; 30: 4833–4844.

    Article  CAS  Google Scholar 

  23. Kuhn PH, Wang H, Dislich B, Colombo A, Zeitschel U, Ellwart JW et al. ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J 2010; 29: 3020–3032.

    Article  CAS  Google Scholar 

  24. Postina R, Schroeder A, Dewachter I, Bohl J, Schmitt U, Kojro E et al. A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J Clin Invest 2004; 113: 1456–1464.

    Article  CAS  Google Scholar 

  25. Wadsworth LP, Lorius N, Donovan NJ, Locascio JJ, Rentz DM, Johnson KA et al. Neuropsychiatric symptoms and global functional impairment along the Alzheimer's continuum. Dement Geriatr Cogn Disord 2012; 34: 96–111.

    Article  Google Scholar 

  26. Raudino F . Non-cognitive symptoms and related conditions in the Alzheimer's disease: a literature review. Neurol Sci 2013; 34: 1275–1282.

    Article  Google Scholar 

  27. Corbett A, Smith J, Creese B, Ballard C . Treatment of behavioral and psychological symptoms of Alzheimer's disease. Curr Treat Options Neurol 2012; 14: 113–125.

    Article  Google Scholar 

  28. Popp J, Arlt S . Pharmacological treatment of dementia and mild cognitive impairment due to Alzheimer's disease. Curr Opin Psychiatry 2011; 24: 556–561.

    Article  Google Scholar 

  29. Cannon TD, Hennah W, van Erp TG, Thompson PM, Lonnqvist J, Huttunen M et al. Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory. Arch Gen Psychiatry 2005; 62: 1205–1213.

    Article  CAS  Google Scholar 

  30. Hashimoto R, Numakawa T, Ohnishi T, Kumamaru E, Yagasaki Y, Ishimoto T et al. Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling. Hum Mol Genet 2006; 15: 3024–3033.

    Article  CAS  Google Scholar 

  31. Thomson PA, Harris SE, Starr JM, Whalley LJ, Porteous DJ, Deary IJ . Association between genotype at an exonic SNP in DISC1 and normal cognitive aging. Neurosci Lett 2005; 389: 41–45.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr Pamela Talalay for critical reading of the manuscript. We thank Mr Yu Taniguchi for technical assistance. We also thank Ms Yukiko Lema for organizing the figures and manuscript. We thank Drs D Selkoe, T Young-Pearse, K Kaibuchi and K Kuroda for the reagents and critical reading of the manuscript. We thank Dr Mattson for his kind gift of 3xTg-AD mice. This work was supported by USPHS grants of MH-084018 (A.S.), MH-094268 Silvo O. Conte center (AS and AK), MH-069853 (AS), MH-085226 (AS), MH-088753 (AS), MH-092443 (AS), MH-091230 (AK), Stanley (AS), RUSK (AS), S-R Foundations (AS), NARSAD (AS, AK, KI and NS), Maryland Stem Cell Research Fund (AS and KI), DoD/CDMRP (TT), CTF-DDI (TT), DFG Ko1679/3-1 (CK), DISCover BMBF 01EW1003 (CK), KNDD/rpAD BMBF 01ED1201B (CK) and the support from Florida state (ISA-5-91351) (SS).

Author information

Author notes

  1. N Shahani

    Present address: 6Current Address: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA,

  2. S Seshadri

    Present address: 7Current Address: Section on Critical Brain Dynamics, National Institute of Mental Health, Bethesda, MD, USA,

  3. Y Hirota-Tsuyada & T Tomoda

    Present address: 8Current Address: Kyoto University School of Medicine, Medical Innovation Center, Kyoto, Japan,

  4. N J Brandon

    Present address: 9Current Address: AstraZeneca Neuroscience iMED, Cambridge, MA, USA,

Authors and Affiliations

  1. Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    N Shahani, S Seshadri, H Jaaro-Peled, K Ishizuka, M Koga, T W Sedlak, A Kamiya & A Sawa

  2. Department of Neurosciences, Beckman Research Institute of City of Hope, Duarte, CA, USA

    Y Hirota-Tsuyada & T Tomoda

  3. Neuroscience Research Unit, Pfizer, Groton, CT, USA

    Q Wang & N J Brandon

  4. Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany

    C Korth

  5. Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA

    S Subramaniam

Authors
  1. N Shahani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Seshadri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H Jaaro-Peled
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K Ishizuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y Hirota-Tsuyada
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Q Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Koga
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. T W Sedlak
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C Korth
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. N J Brandon
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. A Kamiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. S Subramaniam
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. T Tomoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. A Sawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Sawa.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shahani, N., Seshadri, S., Jaaro-Peled, H. et al. DISC1 regulates trafficking and processing of APP and Aβ generation. Mol Psychiatry 20, 874–879 (2015). https://doi.org/10.1038/mp.2014.100

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2014.100

This article is cited by

Search

Advanced search

Quick links