Postnatal disruption of the disintegrin/metalloproteinase ADAM10 in brain causes epileptic seizures, learning deficits, altered spine morphology, and defective synaptic functions

Johannes Prox, Christian Bernreuther, Hermann Altmeppen, Jasper Grende, Markus Glatze, Rudi D'Hooge, Stijn Stroobants, Tariq Ahmed, Detlef Balschun, Michael Willem, Sven Lammich, Dirk Isbrandt, Michaela Schweizer, Katrien Horré, Bart De Strooper, Paul Saftig

Research output: Contribution to journalArticle

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Abstract

The metalloproteinase ADAM10 is of importance for Notch-dependent cortical brain development. The protease is tightly linked with -secretase activity toward the amyloid precursor protein (APP) substrate. Increasing ADAM10 activity is suggested as a therapy to prevent the production of the neurotoxic amyloid β(Aβ) peptide in Alzheimer's disease. To investigate the function of ADAM10 in postnatal brain, we generated Adam10 conditional knock-out (A10cKO) mice using a CaMKIIα-Cre deleter strain. The lack of ADAM10 protein expression was evident in the brain cortex leading to a reduced generation of sAPPβ and increased levels of sAPPβ and endogenous Aβ peptides. The A10cKO mice are characterized by weight loss and increased mortality after weaning associated with seizures. Behavioral comparison of adult mice revealed that the loss of ADAM10 in the A10cKO mice resulted in decreased neuromotor abilities and reduced learning performance, which were associated with altered in vivo network activities in the hippocampal CA1 region and impaired synaptic function. Histological and ultrastructural analysis of ADAM10-depleted brain revealed astrogliosis, microglia activation, and impairednumberand altered morphology of postsynaptic spine structures.Adefect in spine morphology was further supported by a reduction of the expression of NMDA receptors subunit 2A and 2B. The reduced shedding of essential postsynaptic cell adhesion proteins such as N-Cadherin, Nectin-1, andAPPmayexplain the postsynaptic defects and the impaired learning, altered network activity, and synaptic plasticity of the A10cKO mice. Our study reveals that ADAM10 is instrumental for synaptic and neuronal network function in the adult murine brain.

Original languageEnglish
Pages (from-to)12915-12928
Number of pages14
JournalJournal of Neuroscience
Volume33
Issue number32
DOIs
Publication statusPublished - 2013
Externally publishedYes

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Disintegrins
Metalloproteases
Epilepsy
Spine
Knockout Mice
Learning
Brain
Cadherins
Hippocampal CA1 Region
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Amyloid Precursor Protein Secretases
Peptides
Neuronal Plasticity
Aptitude
Amyloid beta-Protein Precursor
Microglia
Weaning
Amyloid
Cell Adhesion
Weight Loss

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Postnatal disruption of the disintegrin/metalloproteinase ADAM10 in brain causes epileptic seizures, learning deficits, altered spine morphology, and defective synaptic functions. / Prox, Johannes; Bernreuther, Christian; Altmeppen, Hermann; Grende, Jasper; Glatze, Markus; D'Hooge, Rudi; Stroobants, Stijn; Ahmed, Tariq; Balschun, Detlef; Willem, Michael; Lammich, Sven; Isbrandt, Dirk; Schweizer, Michaela; Horré, Katrien; De Strooper, Bart; Saftig, Paul.

In: Journal of Neuroscience, Vol. 33, No. 32, 2013, p. 12915-12928.

Research output: Contribution to journalArticle

Prox, J, Bernreuther, C, Altmeppen, H, Grende, J, Glatze, M, D'Hooge, R, Stroobants, S, Ahmed, T, Balschun, D, Willem, M, Lammich, S, Isbrandt, D, Schweizer, M, Horré, K, De Strooper, B & Saftig, P 2013, 'Postnatal disruption of the disintegrin/metalloproteinase ADAM10 in brain causes epileptic seizures, learning deficits, altered spine morphology, and defective synaptic functions', Journal of Neuroscience, vol. 33, no. 32, pp. 12915-12928. https://doi.org/10.1523/JNEUROSCI.5910-12.2013
Prox, Johannes ; Bernreuther, Christian ; Altmeppen, Hermann ; Grende, Jasper ; Glatze, Markus ; D'Hooge, Rudi ; Stroobants, Stijn ; Ahmed, Tariq ; Balschun, Detlef ; Willem, Michael ; Lammich, Sven ; Isbrandt, Dirk ; Schweizer, Michaela ; Horré, Katrien ; De Strooper, Bart ; Saftig, Paul. / Postnatal disruption of the disintegrin/metalloproteinase ADAM10 in brain causes epileptic seizures, learning deficits, altered spine morphology, and defective synaptic functions. In: Journal of Neuroscience. 2013 ; Vol. 33, No. 32. pp. 12915-12928.
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abstract = "The metalloproteinase ADAM10 is of importance for Notch-dependent cortical brain development. The protease is tightly linked with -secretase activity toward the amyloid precursor protein (APP) substrate. Increasing ADAM10 activity is suggested as a therapy to prevent the production of the neurotoxic amyloid β(Aβ) peptide in Alzheimer's disease. To investigate the function of ADAM10 in postnatal brain, we generated Adam10 conditional knock-out (A10cKO) mice using a CaMKIIα-Cre deleter strain. The lack of ADAM10 protein expression was evident in the brain cortex leading to a reduced generation of sAPPβ and increased levels of sAPPβ and endogenous Aβ peptides. The A10cKO mice are characterized by weight loss and increased mortality after weaning associated with seizures. Behavioral comparison of adult mice revealed that the loss of ADAM10 in the A10cKO mice resulted in decreased neuromotor abilities and reduced learning performance, which were associated with altered in vivo network activities in the hippocampal CA1 region and impaired synaptic function. Histological and ultrastructural analysis of ADAM10-depleted brain revealed astrogliosis, microglia activation, and impairednumberand altered morphology of postsynaptic spine structures.Adefect in spine morphology was further supported by a reduction of the expression of NMDA receptors subunit 2A and 2B. The reduced shedding of essential postsynaptic cell adhesion proteins such as N-Cadherin, Nectin-1, andAPPmayexplain the postsynaptic defects and the impaired learning, altered network activity, and synaptic plasticity of the A10cKO mice. Our study reveals that ADAM10 is instrumental for synaptic and neuronal network function in the adult murine brain.",
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AU - Bernreuther, Christian

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AU - Grende, Jasper

AU - Glatze, Markus

AU - D'Hooge, Rudi

AU - Stroobants, Stijn

AU - Ahmed, Tariq

AU - Balschun, Detlef

AU - Willem, Michael

AU - Lammich, Sven

AU - Isbrandt, Dirk

AU - Schweizer, Michaela

AU - Horré, Katrien

AU - De Strooper, Bart

AU - Saftig, Paul

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