{"id":{"repo_id":"cagliari","oai_identifier":"oai:iris.unica.it:11584/356461"},"canonical_url":"https://search.dev.ndltd.org/etd/cagliari/oai:iris.unica.it:11584/356461","repository":{"repo_id":"cagliari","name":"Università di Cagliari","base_url":"https://iris.unica.it/oai/request"},"display":{"title":"Neuropathological role of alpha-synuclein: major contribution of inflammation in the evolution of both motor and non-motor symptoms of Parkinson’s disease","abstract":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["PALMAS, MARIA FRANCESCA"],"institution":"Università degli Studi di Cagliari","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["CARTA, ANNAROSA"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2023,"date_issued":"2023-01-16T00:00:00+01:00","date_published":"2023-01-16T00:00:00+01:00","updated_at":"2026-07-24T01:29:52Z","subjects":["Settore BIO/14 - Farmacologia"],"languages":["eng"],"rights":["info:eu-repo/semantics/openAccess"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/11584/356461","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["CARTA, ANNAROSA"]},{"key":"dc:creator","label":"Author","values":["PALMAS, MARIA FRANCESCA"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2023-01-16T00:00:00+01:00"]},{"key":"dc:publisher","label":"Institution","values":["Università degli Studi di Cagliari"]},{"key":"dc:type","label":"Dc Type","values":["info:eu-repo/semantics/doctoralThesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Settore BIO/14 - Farmacologia"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["info:eu-repo/semantics/openAccess"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/11584/356461"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["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."]},{"key":"dc:title","label":"Title","values":["Neuropathological role of alpha-synuclein: major contribution of inflammation in the evolution of both motor and non-motor symptoms of Parkinson’s disease"]}]}],"canonical_facts":{"dc:contributor":["CARTA, ANNAROSA"],"dc:creator":["PALMAS, MARIA FRANCESCA"],"dc:date":["2023-01-16T00:00:00+01:00"],"dc:description":["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."],"dc:identifier":["https://hdl.handle.net/11584/356461"],"dc:language":["eng"],"dc:publisher":["Università degli Studi di Cagliari"],"dc:rights":["info:eu-repo/semantics/openAccess"],"dc:subject":["Settore BIO/14 - Farmacologia"],"dc:title":["Neuropathological role of alpha-synuclein: major contribution of inflammation in the evolution of both motor and non-motor symptoms of Parkinson’s disease"],"dc:type":["info:eu-repo/semantics/doctoralThesis"]},"updated_at":"2026-07-24T01:29:52Z"}