The Aβ aggregation modulator MRZ-99030 prevents and even reverses synaptotoxic effects of Aβ 1-42 on LTP even following serial dilution to a 500:1 stoichiometric excess of Aβ 1-42 , suggesting a beneficial prion-like seeding mechanism.

MRZ-99030 (GAL-101) is a small molecule that promotes the formation of off-pathway, non-toxic amorphous clusters of A beta thereby reducing the amount of toxic soluble oligomeric A beta species. MRZ-99030 clearly prevents synaptotoxic effects of A beta(1-42) oligomers on synaptic plasticity and cognition. Long lasting in vivo effects indicate that MRZ-99030 seeds a beneficial self-replication of non-toxic A beta aggregates - "trigger effect". To test this, we prepared a serial dilution of MRZ-99030 starting with a 20:1 stoichiometric excess to A beta(1-42). After incubating the A beta(1-42)/MRZ-99030 mixture for 20 min, 10% was transferred to a freshly prepared A beta(1-42) solution. This dilution step was repeated 3 times finally resulting in a 500:1 stoichiometric excess of A beta(1-42) over MRZ-99030. This solution was tested for its ability to impair long-term potentiation (LTP) in CA1 neurons. Even following serial dilution, MRZ-99030 prevented the synaptotoxic effect of A beta(1-42) on CA1-LTP after tetanic stimulation of the Schaffer collaterals whereas incubation with MRZ-99030 (0.1 nM) without serial dilution did not prevent the synaptic deficits caused by A beta(1-42) (50 nM). Time course experiments revealed that this protective effect was still evident even when the serially diluted A beta(1-42)/MRZ-99030 mixture was prepared up to 1 week before the LTP experiment. MRZ-99030, when serially diluted with A beta(1-42), was also capable of detoxifying/reversing an already established neurotoxic process. In TEM experiments, A beta oligomers/annular protofibrils were converted to amorphous A beta clusters following incubation with serially diluted MRZ-99030 to a final concentration of MRZ-99030 (20 nM) and A beta(1-42) (10 mu M).