title: 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.
authors: Department of Anaesthesiology, Technische Universität München, D-81675, Germany.
authors: Gerhard
authors: G
authors: Rammes
authors: Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, D-60318, Frankfurt, Germany.
authors: Andreas
authors: A
authors: Gravius
authors: Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, D-60318, Frankfurt, Germany.
authors: Maarten
authors: M
authors: Ruitenberg
authors: Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, D-60318, Frankfurt, Germany.
authors: Nico
authors: N
authors: Wegener
authors: Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, D-60318, Frankfurt, Germany.
authors: Caroline
authors: C
authors: Chambon
authors: Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, D-60318, Frankfurt, Germany.
authors: Kamila
authors: K
authors: Sroka-Saidi
authors: Neurosolutions Ltd., P.O. Box 3517, Coventry, CV4 7ZS, UK.
authors: Ross
authors: R
authors: Jeggo
authors: Neurosolutions Ltd., P.O. Box 3517, Coventry, CV4 7ZS, UK.
authors: Lydia
authors: L
authors: Staniaszek
authors: 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.
authors: Dave
authors: D
authors: Spanswick
authors: School of Psychology, Queens University, Belfast, BT7 1NN, UK.
authors: Eugene
authors: E
authors: O'Hare
authors: School of Psychology, Queens University, Belfast, BT7 1NN, UK.
authors: Philip
authors: P
authors: Palmer
authors: School of Psychology, University of Ulster, Coleraine, BT52 1SA, UK.
authors: Eun-Mee
authors: EM
authors: Kim
authors: Neurobiology, Biocenter, Ludwig-Maximilians-Universität München, D-82152, Germany.
authors: Wolfgang
authors: W
authors: Bywalez
authors: Neurobiology, Biocenter, Ludwig-Maximilians-Universität München, D-82152, Germany; Neurophysiology, Universität Regensburg, D-93040, Germany.
authors: Veronica
authors: V
authors: Egger
authors: Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, D-60318, Frankfurt, Germany. Electronic address: christopher.parsons@merz.de.
authors: Christopher G
authors: CG
authors: Parsons
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D003216:Conditioning, Operant / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D007294:Inositol / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism* / Q000633:toxicity*; D011699:Putamen / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D021641:Recognition, Psychology / Q000187:drug effects
chemical_list: C000598750:2-(2-amino-3-(1H-indol-3-yl)propionylamino)-2-methylpropionic acid; D016229:Amyloid beta-Peptides; D017077:Culture Media, Conditioned; D004151:Dipeptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C009217:scyllitol; D007294:Inositol; D002118:Calcium
keywords: Aggregation; Alternating lever cyclic ratio schedule (ALCR); Alzheimer's disease; Beta-amyloid; Calcium imaging; Dendritic spines; In vitro; In vivo; Long term potentiation (LTP); Novel object recognition (NOR); Oligomers; Pharmacokinetics; Synaptotoxicity