Synaptic Toxicity of OGA Inhibitors and the Failure of Ceperognastat

AbstractO-GlcNAcase inhibitors (OGAi) have been proposed as therapeutics for Alzheimer’s disease due to their ability to increase O-GlcNAcylation of tau and reduce its aggregation. However, the recent failure of ceperognastat in a Phase II trial—marked by accelerated cognitive decline in the treatment arm—has raised concerns about the safety of this therapeutic class. Here, we evaluated the acute synaptic effects of three structurally distinct OGAi (ceperognastat, ASN90, and MK8719) in mouse hippocampal slices. Electrophysiological recordings revealed that all three compounds impaired both short- and long-term synaptic plasticity, as evidenced by reduced paired-pulse facilitation/depression and suppressed long-term potentiation.Immunohistochemistry showed altered synaptic protein levels, with increased PSD-95 and reduced Synaptophysin 1 in neurons, alongside a biphasic shift in Tau phosphorylation. These findings indicate that OGAi produce rapid and convergent synaptotoxic effects across pre- and postsynaptic compartments, likely reflecting a class-wide mechanism. We argue that electrophysiological screening should be standard in CNS drug development and caution against targeting essential synaptic processes in chronic neurodegenerative conditions.