Positive Allosteric Modulation of the α5-GABAA receptors prevents neuronal atrophy and cognitive decline independently of tau tangle accumulation in the PS19 mouse model

ABSTRACT Background Dysregulated Tau phosphorylation (p-Tau) is a hallmark of neurodegenerative disorders such as Alzheimer’s disease (AD) or frontotemporal dementia (FTD), resulting in neurofibrillary tangle accumulation, neuronal atrophy and cognitive impairment. Impaired somatostatin (SST) expression and reduced SST-expressing GABAergic neurons significantly contributes to AD-related pathophysiology and correlates with cognitive impairment. SST+ interneurons inhibit the dendrites of excitatory neurons in cortical layers and hippocampus, primarily through α5-GABA-A receptors, regulating cognitive function. Leveraging a newly developed small molecule that targets the α5-GABA-A receptors via positive allosteric modulation (α5-PAM), we assessed its effects on p-Tau-related neuronal morphology, cognitive deficits and protein expression. Methods In the PS19 transgenic mouse model, we administered the α5-PAM, GL-II-73, either acutely or chronically at 3 and 6 months, corresponding to early and advanced stage of p-Tau accumulation. Golgi staining analyzed dendritic morphology and spine density in mice chronically exposed to α5-PAM. Western blotting was used to quantify p-tau and Tau expression. Spatial working memory was assessed using the Y-maze. Results Chronic treatment at 3 and 6 months mitigated p-Tau-induced loss of spine density and reduced dendritic length. α5-PAM treatment did not affect p-tau levels. α5-PAM effectively reversed spatial working memory deficits induced by p-tau accumulation both acutely and chronically. Conclusions α5-GABA-A receptor positive allosteric modulation displayed neurotrophic (spine and dendritic pathology) and procognitive (working memory) effects in the PS19 model, independently of p-Tau burden. This suggests a novel therapeutic strategy for p-Tau-related pathologies with both symptomatic and disease-modifying potential.