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
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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Inhibition of GPR17 with cangrelor improves cognitive impairment and synaptic deficits induced by Aβ<inf>1–42</inf> through Nrf2/HO-1 and NF-κB signaling pathway in mice
2021, International ImmunopharmacologyCitation Excerpt :Increasing evidence demonstrates that Aβ has been found to impair memory, induce oxidative stress, neuroinflammation, and inhibit synaptic plasticity [33–35]. It is widely acknowledged that mice i.c.v. injected with Aβ1–42 can mimic some cognitive deficits in AD [6,36,37]. Although this model is unable to induce all the pathological features of AD, the central injection of Aβ peptides is a paradigm that supports the hypothesis of a key pathogenic role of oligomeric Aβ.
The Aβ aggregation modulator MRZ-99030 prevents and even reverses synaptotoxic effects of Aβ<inf>1-42</inf> on LTP even following serial dilution to a 500:1 stoichiometric excess of Aβ<inf>1-42</inf>, suggesting a beneficial prion-like seeding mechanism
2020, NeuropharmacologyCitation Excerpt :In 2015 we characterized MRZ-99030 (previously D-Trp-Aib (Frydman-Marom et al., 2009) now GAL-101) to be a small molecule that promotes the formation of off-pathway, non-toxic aggregates thereby reducing the amount of intermediate toxic soluble oligomeric Aβ1-42 species (Parsons et al., 2015). When applied at a 10:1 stoichiometric excess to Aβ1-42, MRZ-99030 clearly reversed the synaptotoxic effects of Aβ1-42 oligomers on synaptic plasticity and cognitive performance (Rammes et al., 2015). Systemic MRZ-99030 (213 mg/kg s. c) decreased retinal ganglion cell (RGC) apoptosis in the Morrison model of glaucoma assessed 3 weeks after acute administration 24 h before acute episcleral vein occlusion with hypertonic saline (Salt et al., 2014).
The anaesthetic xenon partially restores an amyloid beta-induced impairment in murine hippocampal synaptic plasticity
2019, NeuropharmacologyCitation Excerpt :However, it is a well-established model for analysing Aβ-mediated effects and is well correlated to transgenic AD models (Ma and Klann, 2012). In our experimental setting Aβ oligomerisation occurred during incubation of the slices with the respective monomeric Aβ preparation as shown before by our group (Rammes et al., 2015; Rammes et al., 2011; Yan et al., 2013). This led to a clear LTP impairment induced by both Aβ1-42 and Aβ1-40.
Pridopidine stabilizes mushroom spines in mouse models of Alzheimer's disease by acting on the sigma-1 receptor
2019, Neurobiology of DiseaseCitation Excerpt :We tested whether pridopidine can prevent deficits in LTP caused by Aβ42 oligomer toxicity. In previous publications (Rammes et al., 2015; Rammes et al., 2011) we have demonstrated that application of synthetic Aβ42 oligomers for 90 min to murine hippocampal slices prevents, 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. In the present study, we tested whether pridopidine is able to restore LTP in the presence of such oligomeric Aβ42 preparations.
CNS repurposing - Potential new uses for old drugs: Examples of screens for Alzheimer's disease, Parkinson's disease and spasticity
2019, NeuropharmacologyCitation Excerpt :As such, a more classical phenotypic screening cascade would, in fact, more likely use such an assay as the starting point with a lower number of compounds preselected based on different criteria see e.g. section “compound selection”. The tertiary in vitro assay would then have been β-amyloid oligomer-induced deficits in the induction of long-term potentiation (LTP) in hippocampal slices, which has particular relevance for cognitive deficits in AD (Rammes et al., 2015). The first whole animal step in this screening cascade would then have been reversal of i.c.v. β-amyloid oligomer-induced deficits in the induction LTP in vivo (Rammes et al., 2015).
The NMDA receptor antagonist Radiprodil reverses the synaptotoxic effects of different amyloid-beta (Aβ) species on long-term potentiation (LTP)
2018, NeuropharmacologyCitation Excerpt :Most of the Aβ species tested reduced baseline NMDA-receptor-mediated EPSCs but none had any effect on baseline AMPA-receptor mediated fEPSPs, despite blocking LTP of these responses. This might, by some, be seen as a contradiction between 1) the present data, and perhaps more importantly 2) to our previously published data showing that Aβ1-42 actually increased synaptic Ca2+ levels in murine hippocampal slices (Rammes et al., 2015). However, firstly there is far more consensus in the literature for direct negative effects of Aβ on NMDA receptor function (for one recent extensive review see Danysz and Parsons, 2012) rather than AMPA receptor function (see e.g. recent some reviews from Guntupalli et al., 2016; Jurado, 2017; Tu et al., 2014).