LOSS OF VTA DOPAMINE SIGNALING: IMPLICATIONS FOR NEUROINFLAMMATION IN ALZHEIMER’S DISEASE

Alterations in the Dopaminergic (DAergic) system can be the basis of many pathological manifestations, including neuroinflammation, a key component of neurodegenerative diseases, including Alzheimer’s Disease (AD). Neuroinflammation is characterized by chronic activation of microglia and NLRP3 inflammasome, one of the main mediators of inflammatory processes in AD. Interestingly, important recent works have highlighted the neurotransmitter DA as a direct inhibitor of the NLRP3 inflammasome and the anti-inflammatory effect of DA was observed in microglia acting via D1 receptors. Yet, the relationship between DAergic deficits and neuroinflammation has never been investigated in AD. This is because deficits in DAergic system has been usually considered as a late consequence of AD pathology and Aß load. To this aim we investigate if the vulnerability of the Ventral Tegmental Area (VTA) DAergic system might be considered as one of the main causes of the inflammatory processes that characterize AD pathology. We first investigate in a validated AD mouse model (Tg2576), characterized by loss of VTA DA neurons, the brain inflammation in VTA projecting areas, such as hippocampus, and whether DA loss is involved in this event at pre-plaques state (7 months). In line with the loss of DA innervation in the hippocampus of 7-month-old Tg mice, we found a significant increase of NLRP3 levels, coinciding with microglia activation and proliferation. These data support the hypothesis that neuroinflammation is an early event in AD that can be present at pre-plaque stages. Moreover, an experimental Aβ-independent model was validated to prove that the prolonged loss of DA signaling is sufficient to induce neuroinflammation in the hippocampus. The selective loss of DA neurons was achieved by using a dual viral approach: co-infusion of TH-iCre AAV virus together with the Cre-dependent Caspase-3 virus (AAV-flex-taCasp3-TEVp) under stereotactic control in the VTA of non-AD mice (C57Bl6 mice). So far, our experiments confirm that our viral approach is sufficient to induce a reduced dopaminergic intake in the hippocampus. More interestingly, DA depletion induce neuroinflammation in the hippocampus, such as proliferation, changes in microglia morphology and NLRP3 inflammasome activation, confirming our hypothesis that the neuroinflammatory events usually studied in areas such as hippocampus in Alzheimer's might be a direct consequence of degeneration of dopaminergic nuclei.