ArticleThe journal of prevention of Alzheimer's disease2026
Synaptic toxicity of OGA inhibitors and the failure of ceperognastat.
Article in The journal of prevention of Alzheimer's disease, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Results of the first-in-human, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose study of BIIB113 in healthy volunteers.The journal of prevention of Alzheimer's disease · 2025Trial
- Post-translational modifications as a regulatory code for tau function in health and disease.Frontiers in dementia · 2026Review
- Discovery of Sennoside A as a NaturalResearch (Washington, D.C.) · 2026Article
- From seeds to symptoms: the molecular landscape of tau seeding in Alzheimer's disease.Frontiers in neuroscience · 2026Review
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6 authors.
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Abstract
O-GlcNAcase inhibitors (OGAi) have emerged as a promising therapeutic strategy in Alzheimer's disease (AD) by enhancing O-GlcNAcylation, which competes with tau phosphorylation and reduces tau aggregation. However, the Phase II clinical trial failure of ceperognastat, marked by accelerated cognitive decline in the treatment group, has raised significant safety concerns. Here, we examined the acute synaptic effects of three structurally distinct OGAi compounds-ceperognastat, ASN90, and MK8719-in mouse hippocampal slices. Electrophysiological recordings revealed suppression of both short- and long-term synaptic plasticity, including paired-pulse facilitation/depression and long-term potentiation. Immunohistochemical analysis confirmed disrupted synaptic protein levels (increased PSD-95, reduced Synaptophysin 1) and a biphasic shift in tau phosphorylation. These convergent findings suggest a class-wide synaptotoxic mechanism and call for a great caution in the development of disease-modifying therapies in AD. We argue that preclinical drug screening for synaptic functionality is essential in CNS-targeted therapeutic pipelines.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.