The Small Molecule GAL-201 Efficiently Detoxifies Soluble Amyloid beta Oligomers: New Approach towards Oral Disease-Modifying Treatment of Alzheimer's Disease

Soluble amyloid beta (A beta) oligomers have been shown to be highly toxic to neurons and are considered to be a major cause of the neurodegeneration underlying Alzheimer's disease (AD). That makes soluble A beta oligomers a promising drug target. In addition to eliminating these toxic species from the patients' brain with antibody-based drugs, a new class of drugs is emerging, namely A beta aggregation inhibitors or modulators, which aim to stop the formation of toxic A beta oligomers at the source. Here, pharmacological data of the novel A beta aggregation modulator GAL-201 are presented. This small molecule (288.34 g/mol) exhibits high binding affinity to misfolded A beta(1-42) monomers (K-D = 2.5 +/- 0.6 nM). Pharmacokinetic studies in rats using brain microdialysis are supportive of its oral bioavailability. The A beta oligomer detoxifying potential of GAL-201 has been demonstrated by means of single cell recordings in isolated hippocampal neurons (perforated patch experiments) as well as in vitro and in vivo extracellular monitoring of long-term potentiation (LTP, in rat transverse hippocampal slices), a cellular correlate for synaptic plasticity. Upon preincubation, GAL-201 efficiently prevented the detrimental effect on LTP mediated by A beta(1-42) oligomers. Furthermore, the potential to completely reverse an already established neurotoxic process could also be demonstrated. Of particular note in this context is the self-propagating detoxification potential of GAL-201, leading to a neutralization of A beta oligomer toxicity even if GAL-201 has been stepwise removed from the medium (serial dilution), likely due to prion-like conformational changes in A beta(1-42) monomer aggregates (trigger effect). The authors conclude that the data presented strongly support the further development of GAL-201 as a novel, orally available AD treatment with potentially superior clinical profile.