Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which no cognition-restoring therapies exist. Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain. Increasing evidence suggests a remodeling of the GABAergic system in AD, which might represent an important therapeutic target. An inverse agonist of alpha 5 subunit-containing GABAA receptors (alpha 5GABAARs), 3-(5-Methylisoxazol-3-yl)-6-[(1-methyl-1,2,3-triazol-4-yl)methyloxy]-1,2,4-triazolo[3-a]phthalazine (alpha 5IA) has cognition-enhancing properties. This study aimed to characterize the effects of alpha 5IA on amyloid beta (A beta(1-42))-induced molecular and cellular changes. Mouse primary hippocampal cultures were exposed to either A beta(1-42) alone, or alpha 5IA alone, alpha 5IA with A beta(1-42) or vehicle alone, and changes in cell viability and mRNA expression of several GABAergic signaling components were assessed. Treatment with 100 nM of alpha 5IA reduced A beta(1-42)-induced cell loss by 23.8% (p < 0.0001) after 6 h and by 17.3% after 5 days of treatment (p < 0.0001). Furthermore, we observed an A beta(1-42)-induced increase in ambient GABA levels, as well as upregulated mRNA expression of the GABAAR alpha 2,alpha 5,beta 2/3 subunits and the GABABR R1 and R2 subunits. Such changes in GABARs expression could potentially disrupt inhibitory neurotransmission and normal network activity. Treatment with alpha 5IA restored A beta(1-42)-induced changes in the expression of alpha 5GABAARs. In summary, this compound might hold neuroprotective potential and represent a new therapeutic avenue for AD.