Researchers at the University of Galway have found evidence that targeting inhibitory signaling in the brain may help address cognitive dysfunction in Alzheimer’s disease (AD), a finding that runs counter to current therapeutic approaches that focus on influencing excitatory pathways. The research, published in Neuropharmacology, identifies how modulation of gamma-aminobutyric acid (GABA) signaling can restore disrupted neural balance and improve memory-related function in AD disease models.
“Given the ever-increasing burden of Alzheimer’s disease, the urgent need for the identification of novel targets for the development of disease-modifying therapy is clear,” said senior author Andrea Kwakowsky, PhD, associate professor of pharmacology and lead researcher at the School of Medicine, University of Galway.
Alzheimer’s disease is characterized by progressive cognitive impairment and is associated with hallmark pathological features including β-amyloid (Aβ) plaques and neurofibrillary tangles. In addition to these, disruption of the brain’s excitatory/inhibitory (E/I) balance has gained traction as a central mechanism contributing to memory loss. Today, most approved therapies for AD target excitatory neurotransmitter systems such as cholinergic and glutamatergic pathways, but “the symptomatic relief provided by these therapies is only marginal, and the progression or underlying causes of the disease are not addressed,” the researchers noted.
For their work, the University of Galway team instead focused on the inhibitory side of this balance, specifically the role of gamma-aminobutyric acid (GABA), the brain’s main inhibitory neurotransmitter. GABA regulates neuronal activity and is essential for maintaining stable network function and memory processes. In AD, however, E/I balance becomes dysregulated with increased extracellular GABA—triggered in part by Aβ—leading to overactivation of certain GABA receptors, particularly α5-containing GABA type A receptors (α5-GABA ARs), which are abundant in the hippocampus. The result is a dampening of neuronal signaling and which impairs learning and memory.
“Our research is significant in that it demonstrates that if we block this GABA receptor activity in nerve cells we can reverse Alzheimer-like effects caused by amyloid beta and improve cognitive performance,” Kwakowsky said.
To test whether blocking a5-GGABA A could help restore E/I balance, the team investigated α5IA, an α5-GABA AR-selective inverse agonist. α5IA works by reducing the activity of α5-GABA ARs, which decreases excess tonic inhibition. The data showed that in experimental models of AD, the compound improved long-term potentiation (LTP), a mechanism of synaptic plasticity and memory, reduced abnormal inhibitory conductance, and restored spatial memory performance.
Mechanistically, α5IA appears to act by restoring physiological levels of inhibition in the hippocampus which is critical for memory formation. By reducing excessive tonic inhibition, it rebalances E/I signaling, which allows neuronal circuits to function more effectively. “The data presented here suggest that in both ex vivo and in vivo AD models, α5IA improves cognitive function by restoring CA1 tonic inhibition, thereby re-establishing E/I balance and ameliorating the abnormal hippocampal network activity induced by Aβ1-42,” the researchers wrote.
This new study is the latest to indicate that targeting inhibitory neurotransmission could be an effective treatment approach for AD. Earlier research has shown that α5-GABA AR modulation enhances memory and reduces inhibitory signaling in both animal models and humans. But most of these studies have not directly examined the effect of α5IA in chronic neurodegenerative disease models.
The researchers noted there are some limitations to their work, pointing out that while α5IA improved cognitive outcomes, it did not reverse neuronal loss in vivo, suggesting that its effects may be primarily functional rather than neuroprotective at later stages of AD. Also, variability in drug exposure and timing may influence outcomes. Finally long-term use of α5IA has also been associated with safety concerns at high doses, including renal toxicity, so further research is needed to determine toxicity and dosing regimens and limits.
Nonetheless, the implications of this research indicate there is potential to develop new AD therapies that directly target network dysfunction rather than focusing solely on amyloid accumulation or excitatory signaling. By restoring E/I balance, this approach shows the potential to improve cognitive function even when AD pathology has taken root. The findings could also benefit diagnostic methods, as biomarkers of inhibitory dysfunction or altered GABA signaling could help identify patients who would benefit an approach that rebalances E/I signaling.
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