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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.

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.

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  • Authors+Show Affiliations

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    Department of Anaesthesiology, Technische Universität München, D-81675, Germany.

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    Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, D-60318, Frankfurt, Germany.

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    Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, D-60318, Frankfurt, Germany.

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    Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, D-60318, Frankfurt, Germany.

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    Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, D-60318, Frankfurt, Germany.

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    Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, D-60318, Frankfurt, Germany.

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    Neurosolutions Ltd., P.O. Box 3517, Coventry, CV4 7ZS, UK.

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    Neurosolutions Ltd., P.O. Box 3517, Coventry, CV4 7ZS, UK.

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    Neurosolutions Ltd., P.O. Box 3517, Coventry, CV4 7ZS, UK; Monash University, Department of Physiology, Clayton, Victoria, Australia; Universisty of Warwick Medical School, Coventry, CV4 7AL, UK.

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    School of Psychology, Queens University, Belfast, BT7 1NN, UK.

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    School of Psychology, Queens University, Belfast, BT7 1NN, UK.

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    School of Psychology, University of Ulster, Coleraine, BT52 1SA, UK.

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    Neurobiology, Biocenter, Ludwig-Maximilians-Universität München, D-82152, Germany.

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    Neurobiology, Biocenter, Ludwig-Maximilians-Universität München, D-82152, Germany; Neurophysiology, Universität Regensburg, D-93040, Germany.

    Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, D-60318, Frankfurt, Germany. Electronic address: christopher.parsons@merz.de.

    Source

    Neuropharmacology 92: 2015 May pg 170-82

    MeSH

    Amyloid beta-Peptides
    Animals
    Calcium
    Cognition Disorders
    Conditioning, Operant
    Culture Media, Conditioned
    Dipeptides
    Disease Models, Animal
    Hippocampus
    In Vitro Techniques
    Injections, Intraventricular
    Inositol
    Long-Term Potentiation
    Male
    Mice
    Mice, Inbred C57BL
    Neurons
    Peptide Fragments
    Putamen
    Rats
    Rats, Sprague-Dawley
    Recognition (Psychology)

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    25637092

    Citation

    Rammes, Gerhard, 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, vol. 92, 2015, pp. 170-82.
    Rammes G, Gravius A, Ruitenberg M, 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;92:170-82.
    Rammes, G., Gravius, A., Ruitenberg, M., Wegener, N., Chambon, C., Sroka-Saidi, K., ... Parsons, C. G. (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. Neuropharmacology, 92, pp. 170-82. doi:10.1016/j.neuropharm.2014.12.037.
    Rammes G, 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;92:170-82. PubMed PMID: 25637092.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - 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. AU - Rammes,Gerhard, AU - Gravius,Andreas, AU - Ruitenberg,Maarten, AU - Wegener,Nico, AU - Chambon,Caroline, AU - Sroka-Saidi,Kamila, AU - Jeggo,Ross, AU - Staniaszek,Lydia, AU - Spanswick,Dave, AU - O'Hare,Eugene, AU - Palmer,Philip, AU - Kim,Eun-Mee, AU - Bywalez,Wolfgang, AU - Egger,Veronica, AU - Parsons,Christopher G, Y1 - 2015/01/28/ PY - 2014/09/10/received PY - 2014/11/28/revised PY - 2014/12/02/accepted PY - 2015/2/1/entrez PY - 2015/2/1/pubmed PY - 2015/12/15/medline KW - Aggregation KW - Alternating lever cyclic ratio schedule (ALCR) KW - Alzheimer's disease KW - Beta-amyloid KW - Calcium imaging KW - Dendritic spines KW - In vitro KW - In vivo KW - Long term potentiation (LTP) KW - Novel object recognition (NOR) KW - Oligomers KW - Pharmacokinetics KW - Synaptotoxicity SP - 170 EP - 82 JF - Neuropharmacology JO - Neuropharmacology VL - 92 N2 - 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. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/25637092/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(15)00025-8 DB - PRIME DP - Unbound Medicine ER -