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Neurons Generated from APP/APLP1/APLP2 Triple Knockout Embryonic Stem Cells Behave Normally in Vitro and in Vivo: Lack of Evidence for a Cell Autonomous Role of the Amyloid Precursor Protein in Neuronal Differentiation†

  1. Bruno A. Bergmans1,4,5,
  2. S. Ali M. Shariati1,4,5,
  3. Ron L.P. Habets3,4,5,
  4. Patrik Verstreken3,4,5,
  5. Luc Schoonjans6,
  6. Ulrike Müller7,
  7. Carlos G. Dotti2,4,5,
  8. Bart De Strooper1,4,5,‡,*

Article first published online: 4 JAN 2010

DOI: 10.1002/stem.296

Issue

STEM CELLS

STEM CELLS

Volume 28, Issue 3, pages 399–406, March 2010

Additional Information

How to Cite

Bergmans, B. A., Shariati, S. A. M., Habets, R. L., Verstreken, P., Schoonjans, L., Müller, U., Dotti, C. G. and De Strooper, B. (2010), Neurons Generated from APP/APLP1/APLP2 Triple Knockout Embryonic Stem Cells Behave Normally in Vitro and in Vivo: Lack of Evidence for a Cell Autonomous Role of the Amyloid Precursor Protein in Neuronal Differentiation. STEM CELLS, 28: 399–406. doi: 10.1002/stem.296

Author Information

  1. 1

    Laboratory of Neuronal Cell Biology and Gene Transfer, Leuven, Belgium

  2. 2

    Laboratory of Neuronal Differentiation, Leuven, Belgium

  3. 3

    Laboratory of Neuronal Communication, Leuven, Belgium

  4. 4

    Vlaams Instituut voor Biotechnologie (VIB) Department of Molecular and Developmental Genetics, Leuven, Belgium

  5. 5

    Center of Human Genetics, KULeuven, Leuven, Belgium

  6. 6

    UZ Brussel, Labo Beta Cell Bank, Brussels, Belgium

  7. 7

    Institut für Pharmazie und Molekulare Biotechnologie IPMB, Universität Heidelberg, Heidelberg, Germany

  1. ‡

    Telephone: +32-16-34-62-27; Fax: +32-16-34-71-81

*Laboratory for the research of Neurodegenerative Diseases, Center for Human Genetics, VIB and K.U.Leuven, O&N1 Herestraat 49 box 602, 3000 Leuven, Belgium

  1. †

    Author contributions: B.A.B.: Conception and design, Collection and assembly of data, data analysis and interpretation, manuscript writing; R.H.: Collection and assembly of data, data analysis and interpretation; P.V.: Data analysis and interpretation, final approval of manuscript; C.G.D.: Conception and design, Data analysis and interpretation, final approval of manuscript; L.S.: Provision of study material; U.M.: Conception and design, provision of study material, final approval of manuscript; B.D.S.: Concept and design, data analysis and interpretation, manuscript writing, final approval of manuscript.

Publication History

  1. Issue published online: 24 MAR 2010
  2. Article first published online: 4 JAN 2010
  3. Accepted manuscript online: 4 JAN 2010 12:00AM EST
  4. Manuscript Accepted: 15 DEC 2009
  5. Manuscript Received: 8 SEP 2009

Funded by

  • Fund for Scientific Research Flanders; KULeuven
  • Federal Office for Scientific Affairs, Belgium, a Methusalem grant of the KULeuven. Grant Number: (IUAP P6/43/)
  • VIB
  • Marie Curie Excellence Grant. Grant Number: (MEXT-CT-2006-042267)

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Keywords:

  • Amyloid precursor protein;
  • Embryonic stem cell;
  • Neuronal differentiation;
  • Alzheimer's disease;
  • Glutamatergic neuron;
  • Chimeric mouse

Abstract

Alzheimer's disease amyloid precursor protein (APP) has been implicated in many neurobiologic processes, but supporting evidence remains indirect. Studies are confounded by the existence of two partially redundant APP homologues, APLP1 and APLP2. APP/APLP1/APLP2 triple knockout (APP tKO) mice display cobblestone lissencephaly and are perinatally lethal. To circumvent this problem, we generated APP triple knockout embryonic stem (ES) cells and differentiated these to APP triple knockout neurons in vitro and in vivo. In comparison with wild-type (WT) ES cell-derived neurons, APP tKO neurons formed equally pure neuronal cultures, had unaltered in vitro migratory capacities, had a similar acquisition of polarity, and were capable of extending long neurites and forming active excitatory synapses. These data were confirmed in vivo in chimeric mice with APP tKO neurons expressing the enhanced green fluorescent protein (eGFP) present in a WT background brain. The results suggest that the loss of the APP family of proteins has no major effect on these critical neuronal processes and that the apparent multitude of functions in which APP has been implicated might be characterized by molecular redundancy. Our stem cell culture provides an excellent tool to circumvent the problem of lack of viability of APP/APLP triple knockout mice and will help to explore the function of this intriguing protein further in vitro and in vivo. STEM CELLS 2010;28:399–406

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