Elsevier

Neuropharmacology

Volume 92, May 2015, Pages 170-182
Neuropharmacology

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

https://doi.org/10.1016/j.neuropharm.2014.12.037Get rights and content

Highlights

  • β-amyloid (Aβ) is a major endogenous pathogen in Alzheimer's disease (AD).

  • Soluble Aβ oligomers are the major cause of synaptoxicity/neurodegeneration in AD.

  • MRZ-99030 promotes off-pathway, non-toxic oligomerization of Aβ.

  • MRZ-99030 reversed the synaptotoxic effects of Aβ oligomers in vitro and in vivo.

  • MRZ-99030 ameliorated cognitive deficits in NOR and ALCR tasks.

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 Ca2+ 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 Ca2+ 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.

Section snippets

Animal welfare

All animal experiments were conducted according to the guidelines of the government institution responsible for animal welfare in the respective laboratories European country/county.

Animals

All animal rooms had automatically controlled temperature (21 ± 1 °C), humidity 60% ± 3%, and normal 12-h light/12-h dark cycles. On arrival animals were randomly allocated to treatment groups and evenly distributed throughout the caging system. Domestic quality mains water and standard laboratory food were available ad libitum (except food for alternating lever cyclic ratio – ALCR). Cages, bedding, and water bottles were changed every 2–3 days. After arrival the animals were allowed at least 6

Brain slice preparation

Sagittal hippocampal slices (350 μM thick) were obtained from adult (2 month) C57/Bl6 male mice that were anaesthetized with isoflurane before decapitation. The brain was rapidly removed, and slices were prepared in ice-cold Ringer solution using a vibroslicer. All slices were placed in a holding chamber for at least 60 min and were then transferred to an immersion superfusion chamber (flow rate 1.5 ml/min) for extracellular recordings. The composition of the Ringer solution was 124 mM NaCl,

MRZ 99030 prevents Aβ1-42 oligomer-induced LTP deficits

In a previous publication (Rammes et al., 2011) we have demonstrated that synthetic Aβ1-42 oligomers prepared according to the in vitro methods used in this paper and then applied for 90 min to murine hippocampal slices prevented, in a concentration-dependent manner, the development of CA1-LTP after tetanic stimulation of the Schaffer collaterals with a half maximal inhibitory concentration of around 2 nM (before oligomerization (Rammes et al., 2011). In the present study, we tested whether

Discussion

The current armamentarium approved for the treatment of AD is only clinically proven to provide symptomatic improvement. For example, although memantine is clearly neuroprotective in numerous preclinical AD models, there is insufficient clinical evidence to support the label “disease modifying effects” in humans (Danysz and Parsons, 2012, Parsons et al., 2013, Parsons et al., 2007). Developing brain penetrant, small molecular weight drugs that interfere with Aβ aggregation seems to be an

Acknowledgements

We wish to thank Prof. Ehud Gazit from Tel Aviv University for first bringing our attention to this dipeptide ((R)-(2-[2-Amino-3-(1H-indol-3-yl)-propionylamino]-2-methyl-propionic acid) first synthesized/characterized in his laboratories and for his continuous intellectual support in our preclinical studies.

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