Effects of neuron-specific ADAM10 modulation in an in vivo model of acute excitotoxic stress

A. B. Clement, R. Hanstein, A. Schröder, H. Nagel, K. Endres, F. Fahrenholz, C. Behl

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

A disintegrin and metalloprotease (ADAM) 10 is the main candidate enzyme for the α-secretase processing of the amyloid precursor protein (APP). Neuron-specific ADAM10 overexpression proved beneficial in the APP[V717I] mutant Alzheimer mouse model [Postina R, Schroeder A, Dewachter I, Bohl J, Schmitt U, Kojro E, Prinzen C, Endres K, Hiemke C, Blessing M, Flamez P, Dequenne A, Godaux E, van Leuven F, Fahrenholz F (2004) A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J Clin Invest 113:1456-1464]. Since Alzheimer patients have a high prevalence for epileptic seizures, we investigated the effects of ADAM10 modulation under conditions of experimentally induced epileptic seizures. In this context we also examined whether ADAM10 effects were influenced by APP levels. Therefore we compared severity of kainate-induced seizures, neurodegeneration and inflammation in double transgenic mice overexpressing functional ADAM10 or a dominant negative ADAM10 mutant in the APP[V717I] background with single transgenic ADAM10 modulated mice. Double transgenic dominant negative ADAM10dn/APP[V717I] mice suffered from stronger epileptic seizures, had a longer recovery period and showed more neurodegeneration and glial activation in the hippocampal region than double transgenic mice moderately overexpressing functional ADAM10 (ADAM10mo/APP[V717I]) and APP[V717I] mice with endogenous ADAM10 levels. This suggests that ADAM10 activity is necessary to provide neuroprotection against excitotoxicity in the APP[V717I] mouse model. Interestingly, increased expression of functional ADAM10 above the endogenous level did not correlate with a better protection against seizures and neurodegeneration. Furthermore, ADAM10 dominant negative mice without transgenic APP overexpression (ADAM10dn) were seizing for a shorter time and showed less neuronal cell death and neuroinflammation after kainate injection than wild-type mice, which shows beneficial effects of ADAM10 inhibition in context with neurodegeneration. In contrast, mice with a high ADAM10 overexpression showed more seizures and stronger neuronal damage and inflammation than wild-type mice and mice with moderate ADAM10 overexpression. Hence, additional cleavage products of ADAM10 may counterbalance the neuroprotective effect of α-secretase-cleaved APP in the defense against excitotoxicity. Our findings highlight the need of a careful modulation of ADAM10 activity for neuroprotection depending on substrate availability and on neurotoxic stress conditions.

Original languageEnglish (US)
Pages (from-to)459-468
Number of pages10
JournalNeuroscience
Volume152
Issue number2
DOIs
StatePublished - Mar 18 2008
Externally publishedYes

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Amyloid beta-Protein Precursor
Neurons
Transgenic Mice
Disintegrins
Epilepsy
Amyloid Precursor Protein Secretases
Seizures
Kainic Acid
Metalloproteases
Inflammation
Amyloid Plaques
Neuroprotective Agents
Neuroglia
Hippocampus
Alzheimer Disease
Cell Death
Injections
Enzymes

Keywords

  • Alzheimer's
  • APP
  • neuroprotection
  • oxidative stress
  • seizures

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Clement, A. B., Hanstein, R., Schröder, A., Nagel, H., Endres, K., Fahrenholz, F., & Behl, C. (2008). Effects of neuron-specific ADAM10 modulation in an in vivo model of acute excitotoxic stress. Neuroscience, 152(2), 459-468. https://doi.org/10.1016/j.neuroscience.2007.10.060

Effects of neuron-specific ADAM10 modulation in an in vivo model of acute excitotoxic stress. / Clement, A. B.; Hanstein, R.; Schröder, A.; Nagel, H.; Endres, K.; Fahrenholz, F.; Behl, C.

In: Neuroscience, Vol. 152, No. 2, 18.03.2008, p. 459-468.

Research output: Contribution to journalArticle

Clement, AB, Hanstein, R, Schröder, A, Nagel, H, Endres, K, Fahrenholz, F & Behl, C 2008, 'Effects of neuron-specific ADAM10 modulation in an in vivo model of acute excitotoxic stress', Neuroscience, vol. 152, no. 2, pp. 459-468. https://doi.org/10.1016/j.neuroscience.2007.10.060
Clement AB, Hanstein R, Schröder A, Nagel H, Endres K, Fahrenholz F et al. Effects of neuron-specific ADAM10 modulation in an in vivo model of acute excitotoxic stress. Neuroscience. 2008 Mar 18;152(2):459-468. https://doi.org/10.1016/j.neuroscience.2007.10.060
Clement, A. B. ; Hanstein, R. ; Schröder, A. ; Nagel, H. ; Endres, K. ; Fahrenholz, F. ; Behl, C. / Effects of neuron-specific ADAM10 modulation in an in vivo model of acute excitotoxic stress. In: Neuroscience. 2008 ; Vol. 152, No. 2. pp. 459-468.
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