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Hyperelectrical activity of cerebrocortical and hippocampal circuits is a prominent feature starting at early stages of Alzheimer’s disease (AD). This excessive electrical activity and its associated excitatory/inhibitory (E/I) imbalance result from increased glutamatergic signaling and dysfunctional GABAergic inhibitory responses. The hyperactive glutamatergic signaling is in part due to overstimulation of extrasynaptic NMDA receptors (NMDARs), which contributes to synaptic loss and subsequent neuronal cell death. In contrast, physiological synaptic (s)NMDAR signaling is important for neuronal survival and normal brain function. Thus, selective inhibition of eNMDARs represents an important therapeutic target. Accordingly, uncompetitive, open-channel blockers like memantine have offered some benefit, but the improved, dual action antagonist, NitroSynapsin (aka NitroMemantine or EM- 036), is far more efficacious in alleviating toxic effects of aberrant glutamatergic signaling while sparing normal synaptic activity in multiple AD model systems, including human AD patient induced pluripotent stem cell (hiPSC)-derived cerebral organoids. Given this class of compounds can rescue synpases in these AD models, they offer the hope of a robust disease-modifying therapy for AD.

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Potential Disease-Modifying Pharmacological Therapy for Alzheimer’s Disease by Protecting Synapses Via Prevention of Hyperexcitability and E/I Imbalance

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  • 发表日期：

    2025年

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  • Swagata Ghatak,
  • Stuart A. Lipton

摘要

Hyperelectrical activity of cerebrocortical and hippocampal circuits is a prominent feature starting at early stages of Alzheimer’s disease (AD). This excessive electrical activity and its associated excitatory/inhibitory (E/I) imbalance result from increased glutamatergic signaling and dysfunctional GABAergic inhibitory responses. The hyperactive glutamatergic signaling is in part due to overstimulation of extrasynaptic NMDA receptors (NMDARs), which contributes to synaptic loss and subsequent neuronal cell death. In contrast, physiological synaptic (s)NMDAR signaling is important for neuronal survival and normal brain function. Thus, selective inhibition of eNMDARs represents an important therapeutic target. Accordingly, uncompetitive, open-channel blockers like memantine have offered some benefit, but the improved, dual action antagonist, NitroSynapsin (aka NitroMemantine or EM- 036), is far more efficacious in alleviating toxic effects of aberrant glutamatergic signaling while sparing normal synaptic activity in multiple AD model systems, including human AD patient induced pluripotent stem cell (hiPSC)-derived cerebral organoids. Given this class of compounds can rescue synpases in these AD models, they offer the hope of a robust disease-modifying therapy for AD.