Abstract:
Alzheimer’s disease (AD) is a complex, progressive and chronic neurodegenerative disorder affecting millions of people worldwide. Data gathered from animal models and human studies have shown that amyloid beta (Aβ), -the up-stream triggering factor of the AD pathophysiology in the Aβ cascade-, directly and/or indirectly promote tau pathology, neuroinflammation, compromises the integrity of the blood brain barrier (BBB), causes excitatory pyramidal and GABAergic interneurons loss, along with synaptic dysfunction and hippocampal excitatory/inhibitory (E/I) balance dysfunction. Early hippocampal network dysfunction is one of the main factors associated with cognitive decline in AD. Increasing evidence demonstrates that the remodelling of the GABAergic system contributing to the E/I disruption in the AD hippocampus. Hence, the GABAergic system rises as an important therapeutic target. In particular, increased extrasynaptic GABAergic tonic inhibition mediated by α5 subunitcontaining GABAA (α5-GABAA) receptors in the hippocampus, significantly contributes to circuit dysfunction and cognitive impairment in AD. The compound, 3-(5-methylisoxazol-3-yl)-6-[(1-methyl1,2,3-triazol-4-yl)methyloxy]-1,2,4-triazolo[3,4-a]phthalazine (α5IA) -an inverse agonist of α5- GABAAR, has shown cognition-enhancing properties in previous studies. The aim of this thesis was to determine the effect of α5IA treatment on Aβ1-42-induced cell loss in the mouse hippocampus and its effect on cognitive-behavioural changes in an in vivo AD mouse model, as well as on tonic inhibition in hippocampal neurons. Moreover, we aimed to examine the effect of α5IA treatment on Aβ1-42-induced changes in the expression and composition of GABAAR subunits in the mouse hippocampus. We provide evidence of the profound plasticity of the GABAAR subunit composition in Aβ1-42-injected mice, as well as in the human AD hippocampus. At 30 days after the Aβ injection, down-regulation of α1-, α5- and β3-subunit expression was observed in the hippocampus of the mice. The γ2 subunit, however, was found to be up-regulated in the dentate gyrus (DG). We also found Aβ1-42-induced local excitatory pyramidal cell loss, neuroinflammation and vascular disruption in Aβ1-42-injected mice, at post-injection day 30. Importantly, Aβ1-42-injected mice showed impaired long-term spatial-memory. Treatment of Aβ1-42-injected mice with 5IA resulted in the modulation of increased tonic GABAergic conductance. The α5IA-mediated decrease in extrasynaptic tonic conductance restored both, Aβ1-42- induced GABAAR subunit expression changes and enhanced tonic conductance in the hippocampus of the mice. These effects of α5IA on cognitive improvement might occur through the restoration of the early altered E/I balance and network circuity in the AD hippocampus, as well as the reduction of inflammation. Subsequently, these molecular effects translate into improved long-term spatial-memory in α5IA–treated mice. Based on these promising results, further investigations should be conducted to assess the effectiveness of α5IA in AD patients.