Positive allosteric modulation of α5-GABA A Receptor in the 5XFAD mouse model has cognitive and neurotrophic benefits

Abstract

Alzheimer’s disease (AD) clinically presents with significant cognitive deficits in memory and executive function while pathologically displaying neuronal atrophy, the buildup of amyloid beta plaques and the presence of neurofibrillary tangles. Current therapies have modest effects on cognition and no effect on neurodegeneration. In AD, the GABAergic system shows reduced neuron populations, less GABA release and altered GABAA receptor (GABAAR) functioning. GABAergic somatostatin (SST) interneurons are particularly vulnerable. These SST cells target GABAAR’s containing the α5 subunit which are linked to cognition, but remain untargeted for therapeutic interventions. When lost, SST interneurons no longer coordinate signals and this presents as cognitive impairment. Using α5-GABAAR positive allosteric modulation (α5-PAM), there is the potential to restore their signaling and improve cognitive performance despite the presence of amyloid. Here we tested a selective α5-PAM (GL-II-73) at early (2 months) and late (5 months) stages of amyloid progression using the 5XFAD model for cognitive benefits, neurotrophic effects and amyloid clearance ability (N=48/study; 50% female). We found age-dependent deficits in spatial working memory and GL-II-73 dose dependently improves this deficit at 5 months of age. Chronic treatment with GL-II-73 showed spine density, spine count and dendritic length recovery at both time points. However, amyloid deposition progressed with age, and GL-II-73 did not have an effect on amyloid build up, suggesting that the effects observed are directly due to the impact of GL-II-73 on α5-GABAARs, and not related to amyloid plaques. These results show that despite the presence of amyloid GL-II-73’s α5-PAM activity overcomes cognitive deficits even at later stages of amyloid progression and demonstrates neurotrophic effects. Overall, results support GL-II-73 and its selective α5-PAM activity as a promising therapeutic option for cognitive deficits in AD.