MRZ-99030 - A novel modulator of Aβ aggregation: II - Reversal of Aβ oligomer-induced deficits in long-term potentiation (LTP) and cognitive performance in rats and mice. - Aix-Marseille Université Access content directly
Journal Articles Neuropharmacology Year : 2015

MRZ-99030 - A novel modulator of Aβ aggregation: II - Reversal of Aβ oligomer-induced deficits in long-term potentiation (LTP) and cognitive performance in rats and mice.

Gerhard Rammes
  • Function : Author
Andreas Gravius
  • Function : Author
Maarten Ruitenberg
  • Function : Author
Nico Wegener
  • Function : Author
Kamila Sroka-Saidi
  • Function : Author
Ross Jeggo
  • Function : Author
Lydia Staniaszek
  • Function : Author
Dave Spanswick
  • Function : Author
Eugene O'Hare
  • Function : Author
Philip Palmer
  • Function : Author
Eun-Mee Kim
  • Function : Author
Wolfgang Bywalez
  • Function : Author
Veronica Egger
  • Function : Author
Christopher G. Parsons
  • Function : Author

Abstract

β-amyloid1-42 (Aβ1-42) is a major endogenous pathogen underlying the aetiology of Alzheimer's disease (AD). Recent evidence indicates that soluble Aβ oligomers, rather than plaques, are the major cause of synaptic dysfunction and neurodegeneration. Small molecules that suppress Aβ aggregation, reduce oligomer stability or promote off-pathway non-toxic oligomerization represent a promising alternative strategy for neuroprotection in AD. MRZ-99030 was recently identified as a dipeptide that modulates Aβ1-42 aggregation by triggering a non-amyloidogenic aggregation pathway, thereby reducing the amount of intermediate toxic soluble oligomeric Aβ species. The present study evaluated the relevance of these promising results with MRZ-99030 under pathophysiological conditions i.e. against the synaptotoxic effects of Aβ oligomers on hippocampal long term potentiation (LTP) and two different memory tasks. Aβ1-42 interferes with the glutamatergic system and with neuronal Ca(2+) signalling and abolishes the induction of LTP. Here we demonstrate that MRZ-99030 (100-500 nM) at a 10:1 stoichiometric excess to Aβ clearly reversed the synaptotoxic effects of Aβ1-42 oligomers on CA1-LTP in murine hippocampal slices. Co-application of MRZ-99030 also prevented the two-fold increase in resting Ca(2+) levels in pyramidal neuron dendrites and spines triggered by Aβ1-42 oligomers. In anaesthetized rats, pre-administration of MRZ-99030 (50 mg/kg s.c.) protected against deficits in hippocampal LTP following i.c.v. injection of oligomeric Aβ1-42. Furthermore, similar treatment significantly ameliorated cognitive deficits in an object recognition task and under an alternating lever cyclic ratio schedule after the i.c.v. application of Aβ1-42 and 7PA2 conditioned medium, respectively. Altogether, these results demonstrate the potential therapeutic benefit of MRZ-99030 in AD.
No file

Dates and versions

hal-01441749 , version 1 (20-01-2017)

Identifiers

Cite

Gerhard Rammes, Andreas Gravius, Maarten Ruitenberg, Nico Wegener, Caroline Chambon, et al.. MRZ-99030 - A novel modulator of Aβ aggregation: II - Reversal of Aβ oligomer-induced deficits in long-term potentiation (LTP) and cognitive performance in rats and mice.. Neuropharmacology, 2015, ⟨10.1016/j.neuropharm.2014.12.037⟩. ⟨hal-01441749⟩

Collections

CNRS UNIV-AMU LNIA
923 View
0 Download

Altmetric

Share

Gmail Facebook X LinkedIn More