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2008-05-01 - Article/Dans un journal avec peer-review - Anglais - 14 page(s)

Dewachter Ilse, Ris Laurence , Croes S., Borghgraef P., Devijver H., Voets T., Nilius B., Godaux Emile, Van Leuven Fred, "Modulation of synaptic plasticity and Tau phosphorylation by wild-type and mutant presenilin1" in Neurobiology of Aging, 29, 5, 639-652

  • Edition : Elsevier, New York (NY)
  • Codes CREF : Neurophysiologie (DI3224)
  • Unités de recherche UMONS : Neurosciences (M119)
Texte intégral :

Abstract(s) :

(Anglais) The function of presenilin1 (PS1) in intra-membrane proteolysis is undisputed, as is its role in neurodegeneration in FAD, in contrast to its exact function in normal conditions. In this study, we analyzed synaptic plasticity and its underlying mechanisms biochemically in brain of mice with a neuron-specific deficiency in PS1 (PS1(n-/-)) and compared them to mice that expressed human mutant PS1[A246E] or wild-type PS1. PS1(n-/-) mice displayed a subtle impairment in Schaffer collateral hippocampal long-term potentiation (LTP) as opposed to normal LTP in wild-type PS1 mice, and a facilitated LTP in mutant PS1[A246E] mice. This finding correlated with, respectively, increased and reduced NMDA receptor responses in PS1[A246E] mice and PS1(n-/-) mice in hippocampal slices. Postsynaptically, levels of NR1/NR2B NMDA-receptor subunits and activated alpha-CaMKII were reduced in PS1(n-/-) mice, while increased in PS1[A246E] mice. In addition, PS1(n-/-) mice, displayed reduced paired pulse facilitation, increased synaptic fatigue and lower number of total and docked synaptic vesicles, implying a presynaptic function for wild-type presenilin1, unaffected by the mutation in PS1[A246E] mice. In contrast to the deficiency in PS1, mutant PS1 activated GSK-3beta by decreasing phosphorylation on Ser-9, which correlated with increased phosphorylation of protein tau at Ser-396-Ser-404 (PHF1/AD2 epitope). The synaptic functions of PS1, exerted on presynaptic vesicles and on postsynaptic NMDA-receptor activity, were concluded to be independent of alterations in GSK-3beta activity and phosphorylation of protein tau.

Identifiants :
  • DOI : 10.1016/j.neurobiolaging.2006.11.019
  • PMID : 17222948