An α5 GABAA Receptor Inverse Agonist, α5IA, Attenuates Amyloid Beta-Induced Neuronal Death in Mouse Hippocampal Cultures

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 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–a]phthalazine (α5IA) has cognition-enhancing properties. This study aimed to characterize the effects of α5IA on amyloid beta (Aβ1–42)-induced molecular and cellular changes. Mouse primary hippocampal cultures were exposed to either Aβ1-42 alone, or α5IA alone, α5IA with Aβ1–42 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 Aβ1–42-induced cell loss by 23.8% (p p 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 Aβ1-42-induced changes in the expression of α5GABAARs. In summary, this compound might hold neuroprotective potential and represent a new therapeutic avenue for AD.

Keywords

• Alzheimer’s disease
• GABA
• α5 GABAA receptors
• α5IA