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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 α5 subunit-containing GABAA receptors (α5GABAARs), 3-(5-Methylisoxazol-3-yl)-6-[(1-methyl-1,2,3-triazol-4-yl)methyloxy]-1,2,4-triazolo[3–<i>a</i>]phthalazine (α5IA) has cognition-enhancing properties. This study aimed to characterize the effects of α5IA on amyloid beta (Aβ_1–42)-induced molecular and cellular changes. Mouse primary hippocampal cultures were exposed to either Aβ_1-42 alone, or α5IA alone, α5IA with Aβ_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 α5IA reduced Aβ_1–42-induced cell loss by 23.8% (<i>p</i> < 0.0001) after 6 h and by 17.3% after 5 days of treatment (<i>p</i> < 0.0001). Furthermore, we observed an Aβ_1-42-induced increase in ambient GABA levels, as well as upregulated mRNA expression of the GABAAR α2,α5,β2/3 subunits and the GABABR R1 and R2 subunits. Such changes in GABARs expression could potentially disrupt inhibitory neurotransmission and normal network activity. Treatment with α5IA restored Aβ_1-42-induced changes in the expression of α5GABAARs. In summary, this compound might hold neuroprotective potential and represent a new therapeutic avenue for AD.