Neuropathological role of alpha-synuclein: major contribution of inflammation in the evolution of both motor and non-motor symptoms of Parkinson’s disease
Neuroinflammation is nowadays considered a cardinal pathological feature of Parkinson’s disease (PD), in which glial cells lose their homeostatic function in favour of a pro-inflammatory profile. Such sustained glial response within the brain parenchyma is characterized by a chronic release of a number of pro-inflammatory mediators, likely driven by pathological interactions with toxic forms of α-Synuclein (αSyn). Moreover, the contribution of the peripheral immune system to PD neuropathology has been demonstrated, promoting the view of PD as a systemic pathology. While the contribution of inflammation to the neuropathology of motor symptoms has been ascertained, its role in non-motor symptoms is still under-investigated, particularly in relation to cognitive disturbances. Here, we targeted inflammation in PD by testing the immunomodulatory imide drug (IMiD) Pomalidomide (Pom) for its disease-modifying properties against motor deficits in a translational rat model of PD based on the intranigral infusion of toxic oligomers of human α-synuclein (H-αSynOs) (study I). Moreover, we investigated the contribution of neuroinflammation in PD cognitive symptoms, in the same PD preclinical model (study II). Study I: The neuroprotective effect of Pom (20 mg/kg; i.p. three times/week for two months) was tested in the early stage of the disease. We found that the infusion of H-αSynOs induced an impairment in motor performance that was fully rescued by Pom, as assessed via a battery of motor tests. Moreover, H-αSynOs-infused rats displayed a 40–45% cell loss within the substantia nigra (SN), that was largely abolished by Pom. The inflammatory response to H-αSynOs infusion and the Pom treatment was evaluated both in CNS and peripherally. After H-αSynOs infusion, microglia displayed a proinflammatory profile, producing a large amount of the cytokine Tumour Necrosis Factor (TNF)-α. In contrast, Pom inhibited the TNF-α overproduction and elevated the anti-inflammatory cytokine Interleukin (IL)-10. Moreover, the H-αSynOs infusion induced a systemic inflammation with a dysregulated production of serum cytokines and chemokines, that was largely restored by Pom. Study II: We asked whether the H-αSynOs-based model of PD is an effective tool to study PD-related cognitive disturbances, thus investigating the contribution of neuroinflammation. We show that H-αSynOs-infused rats displayed memory deficits three months after the infusion. These were underpinned by an altered electrophysiological neuronal activity and altered expression of the neuron-specific immediate early gene (IEG) Npas4 (Neuronal PAS domain protein 4) in cognitive regions, such as the anterior cingulate cortex (ACC). Moreover, the brain of cognitively impaired rats showed a neuroinflammatory response in the ACC and discrete subareas of the hippocampus, in the absence of any evident neuronal loss, supporting a role of neuroinflammation in cognitive decline. Such neuroinflammatory response was epitomized by the acquisition of a pro-inflammatory phenotype by microglia cells, as indicated by the increased levels of TNF-α. Taken together, results of the present study indicate that neuroinflammation is a common feature of both motor and non-motor aspects of PD, and suggest that targeting inflammation might represent a novel therapeutic strategy to treat the disease as a whole.
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