Procognitive and neurotrophic benefits of α5-GABA-A receptor positive allosteric modulation in a β-amyloid deposition model of Alzheimer’s disease pathology

INTRODUCTION Reduced somatostatin (SST) and SST-expressing GABAergic neurons are well-replicated findings in Alzheimer’s disease (AD) and are associated with cognitive deficits. SST cells inhibit pyramidal cell dendrites through α5-GABA-A receptors (α5-GABAA-R). α5-GABAAR positive allosteric modulation (α5-PAM) has procognitive and neurotrophic effects in stress and aging models. METHODS We tested whether α5-PAM (GL-II-73) could reverse cognitive deficits and neuronal spine loss in early and late stages of β-amyloid deposition in the 5xFAD model (N=48/study; 50% female). RESULTS Acute or chronic administration of GL-II-73 reversed spatial working memory in 5xFAD mice at 2 and 5 months of age. Chronic GL-II-73 treatment reversed 5xFAD-induced loss of spine density, spine count and dendritic length at both time points, despite β-amyloid accumulation. DISCUSSION These results demonstrate procognitive and neurotrophic effects of GL-II-73 in early and late stages of Alzheimer-related β-amyloid deposition. This suggests α5-PAM as a novel β-amyloid-independent symptomatic therapeutic approach. ### 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. AB, KW, KP and DS declare no conflicts of interest.