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

Dharavath, R. N.; Bernardo, A.; Marceau-Linhares, C.; Marcotte, M.; Wong, K.; Pina-Leblanc, C.; Bouchet, A.; Sharmin, D.; Cook, J.; Pandey, K. P.; Prevot, T. D.; Sibille, E.

doi:10.1101/2024.09.07.611810

bioRxiv · 10.1101/2024.09.07.611810

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

Dharavath, R. N.·Bernardo, A.·Marceau-Linhares, C.·Marcotte, M.·Wong, K.·Pina-Leblanc, C.·Bouchet, A.·Sharmin, D.·Cook, J.·Pandey, K. P.·Prevot, T. D.·Sibille, E.

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Abstract

BackgroundDysregulated Tau phosphorylation (p-Tau) is a hallmark of neurodegenerative disorders such as Alzheimers 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 5-GABA-A receptors, regulating cognitive function. Leveraging a newly developed small molecule that targets the 5-GABA-A receptors via positive allosteric modulation (5-PAM), we assessed its effects on p-Tau-related neuronal morphology, cognitive deficits and protein expression. MethodsIn the PS19 transgenic mouse model, we administered the 5-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 5-PAM. Western blotting was used to quantify p-tau and Tau expression. Spatial working memory was assessed using the Y-maze. ResultsChronic treatment at 3 and 6 months mitigated p-Tau-induced loss of spine density and reduced dendritic length. 5-PAM treatment did not affect p-tau levels. 5-PAM effectively reversed spatial working memory deficits induced by p-tau accumulation both acutely and chronically. Conclusions5-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.

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Dharavath, R. N., Bernardo, A., Marceau-Linhares, C., Marcotte, M., Wong, K., Pina-Leblanc, C., Bouchet, A., Sharmin, D., Cook, J., Pandey, K. P., Prevot, T. D., Sibille, E.. 2024-09-12. Positive Allosteric Modulation of the α5-GABAA receptors prevents neuronal atrophy and cognitive decline independently of tau tangle accumulation in the PS19 mouse model. https://doi.org/10.1101/2024.09.07.611810

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