Positive Allosteric Modulation of the Α5-Gabaa Receptors Prevents Neuronal Atrophy and Cognitive Decline Independently of Tau Tangle Accumulation in the PS19 Mouse Model

Background Dysregulated tau phosphorylation is one of the hallmarks of Alzheimer’s disease (AD), and it results in cognitive impairments, neuronal atrophy, and neurofibrillary tangle accumulation. Evidence shows that impaired somatostatin (SST) expression, particularly in SST-expressing GABAergic neurons, significantly contributes to AD-related pathophysiology and may increase cognitive burden. Additionally, SST+ interneurons in cortical layers and the hippocampus inhibit the dendrites of excitatory neurons, primarily through α5-GABAA receptors involved in cognitive regulation. Leveraging the potential of a newly developed small molecule that targets the α5-GABAA receptors via positive allosteric modulation (α5-PAM), we aim to assess its effects on tau phosphorylation-related neuronal morphology, cognitive deficits and protein expression. Methods In the PS19 transgenic mouse mode, we administered the α5-PAM, GL-II-73, either acutely or chronically at 3 and 6 months. We assessed spatial working memory using the Y-maze. Golgi staining analyzed dendritic morphology in chronically exposed mice to α5-PAM. Western blotting was used to quantify p-Tau and Tau expression. Results α5-PAM effectively reverses spatial working memory deficits induced by tau phosphorylation both acutely and chronically. Chronic treatment at 3and 6 months mitigates tau-induced loss of spine density. However, α5-PAM does not directly influence p-Tau levels, suggesting cognitive and neurotrophic benefits of GL-II-73s are independent of Tau burden. Conclusions These results demonstrate the potential for both symptomatic and disease-modifying effects, highlighting the promise of α5-GABAA receptor positive allosteric modulation as a novel therapeutic strategy for addressing cognitive deficits associated with tau phosphorylation in AD pathology. ### Competing Interest Statement JMC, MM, ES and TP are listed inventors on patents covering syntheses and use of the compound. ES is Founder and CSO of Damona Pharmaceuticals, a biopharma dedicated to bring novel GABAergic compounds to the clinic. TP is the acting Director of Preclinical Research and Development in Damona. All other authors declare no conflicts of interest.