GAL-201 as a Promising Amyloid-β-Targeting Small-Molecule Approach for Alzheimer’s Disease Treatment: Consistent Effects on Synaptic Plasticity, Behavior and Neuroinflammation

TL;DR

GAL-201 is a promising Alzheimer’s treatment that prevents toxic amyloid-beta oligomers, protecting brain cells and improving learning in mice.

Contribution

GAL-201 shows consistent neuroprotection and anti-inflammatory effects across multiple Aβ isoforms and models.

Findings

GAL-201 prevents Aβ oligomer formation and protects synaptic plasticity for up to a week.

GAL-201 reduces Aβ-induced spine loss and proinflammatory microglia and astrocyte activation.

GAL-201 improves spatial learning in an Alzheimer’s mouse model and alters Aβ deposition patterns.

Abstract

Soluble oligomeric forms of Amyloid-β (Aβ) are considered the major toxic species leading to the neurodegeneration underlying Alzheimer’s disease (AD). Therefore, drugs that prevent oligomer formation might be promising. The atypical dipeptide GAL-201 is orally bioavailable and interferes as a modulator of Aβ aggregation. It binds to aggregation-prone, misfolded Aβ monomers with high selectivity and affinity, thereby preventing the formation of toxic oligomers. Here, we demonstrate that the previously observed protective effect of GAL-201 on synaptic plasticity occurs irrespective of shortages and post-translational modifications (tested isoforms: Aβ1–42, Aβ(p3-42), Aβ1–40 and 3NTyr(10)-Aβ). Interestingly, the neuroprotective activity of a single dose of GAL-201 was still present after one week and correlated with a prevention of Aβ-induced spine loss. Furthermore, we could observe beneficial effects on spine morphology as well as the significantly reduced activation of proinflammatory microglia and astrocytes in the presence of an Aβ1–42-derived toxicity. In line with these in vitro data, GAL-201 additionally improved hippocampus-dependent spatial learning in the “tgArcSwe” AD mouse model after a single subcutaneous administration. By this means, we observed changes in the deposition pattern: through the clustering of misfolded monomers as off-pathway non-toxic Aβ agglomerates, toxic oligomers are removed. Our results are in line with previously collected preclinical data and warrant the initiation of Investigational New Drug (IND)-enabling studies for GAL-201. By demonstrating the highly efficient detoxification of β-sheet monomers, leading to the neutralization of Aβ oligomer toxicity, GAL-201 represents a promising drug candidate against Aβ-derived pathophysiology present in AD.

Figures