Sodium Oligomannate Electrostatically Binds to Aβ and Blocks Its Aggregation.

Abstract

GV-971 (sodium oligomannate) is a China Food and Drug Administration (CFDA)-approved drug for treating Alzheimer's disease, and it could inhibit Aβ fibril formation in vitro and in mouse studies. To elucidate the mechanisms for understanding how GV-971 modulates Aβ's aggregation, we conducted a systematic biochemical and biophysical study of Aβ40/Aβ42:GV-971 systems. The integrating analysis of previously published data and our results suggests that the multisite electrostatic interactions between GV-971's carboxylic groups and Aβ40/Aβ42's three histidine residues might play a dominant role in driving the binding of GV-971 to Aβ. The fuzzy-type electrostatic interactions between GV-971 and Aβ are expected to protect Aβ from aggregation potentially through breaking the histidine-mediated inter-Aβ electrostatic interactions. Meanwhile, since GV-971's binding exhibited a slight downregulation effect on the flexibility of Aβ's histidine-colonized fragment, which potentially favors Aβ aggregation, we conclude that the dynamics alteration plays a minor role in GV-971's modulation on Aβ aggregation.