Focusing on altered neuronal networks to fight early deficits in a mouse model of Alzheimer’s Disease

Although the most accredited hypothesis of neurodegeration is still based on the toxicity induced by amyloid plaques, there are still no effective therapeutic options for the treatment of Alzheimer’s Disease (AD). Recently, a part of the scientific world has evaluated the role of the mesocorticolimbic system in the onset of the disease. Numerous clinical and preclinical studies, in fact, have demonstrated a progressive disconnection of the ventral tegmental area (VTA) with its projection areas, including the hippocampus, depriving their neuronal populations of an essential neurotransmitter, dopamine. In the animal model of AD, Tg2576, we demonstrated a progressive death of VTA dopaminergic neurons, whose consequent hippocampal denervation causes functional alterations in a specific cell type, the gabaergic interneurons. The latter are responsible for the generation of gamma oscillations, crucial for cognitive and memory processes, which are also altered in our AD model. Therefore, the aim was to investigate the high susceptibility of VTA dopaminergic neurons in the Tg2576 model, using molecular biology, electrophysiological and calcium imaging techniques. In fact, we have demonstrated greater hyperexcitability of the VTA, as a plausible sign of neuronal suffering, together with an increase in the expression of calcium-binding proteins in dopaminergic neurons to buffer the increase in intracellular concentration. These results demonstrate that surviving dopaminergic neurons implement compensatory mechanisms for at their survival. In parallel, we evaluated the electrophysiological characteristics of gabaergic interneurons, demonstrating lower excitability resulting in a reduction in inhibitory tone on pyramidal neurons in the hippocampus. We next evaluated the effects of a transcranial alternating current stimulation (tACS) protocol in the hippocampus in the gamma range. The stimulation resulted in the restoration of long-term hippocampal potentiation, together with an improvement in cognitive performance, characteristics notoriously reduced in our AD model. The treatment represents a valid alternative to the pharmacological therapies currently in use, allowing the restoration of the hippocampal alterations, at least in part, attributed to the reduction of DA.