{"title":"血管紧张素(1-7)糖肽 PNA5 可通过调节神经炎症改善帕金森病慢性进行性小鼠模型的认知能力。","authors":"","doi":"10.1016/j.expneurol.2024.114926","DOIUrl":null,"url":null,"abstract":"<div><p>Cognitive decline in Parkinson's Disease (PD) is a prevalent and undertreated aspect of disease. Currently, no therapeutics adequately improve this aspect of disease. It has been previously shown that MAS receptor agonism via the glycosylated Angiotensin (1–7) peptide, PNA5, effectively reduces cognitive decline in models of vascular contributions to cognitive impairment and dementia (VCID). PNA5 has a brain/plasma ratio of 0.255 indicating good brain penetration. The goal of the present study was to determine if (1) systemic administration of PNA5 rescued cognitive decline in a mouse model of PD, and (2) if improvements in cognitive status could be correlated with changes to histopathological or blood plasma-based changes. Mice over-expressing human, wild-type α-synuclein (αSyn) under the Thy1 promoter (Thy1-αSyn mice, “line 61”) were used as a model of PD with cognitive decline. Thy1-αSyn mice were treated with a systemic dose of PNA5, or saline (1 mg/kg/day) beginning at 4 months of age and underwent behavioral testing at 6 months, compared to WT. Subsequently, mice brains were analyzed for changes to brain pathology, and blood plasma was examined with a Multiplex Immunoassay for peripheral cytokine changes. Treatment with PNA5 reversed cognitive dysfunction measured by Novel Object Recognition and spontaneous alteration in a Y-maze in Thy1-αSyn mice. PNA5 treatment was specific to cognitive deficits, as fine-motor disturbances were unchanged. Enhanced cognition was associated with decreases in hippocampal inflammation and reductions in circulating levels of Macrophage Induced Protein (MIP-1β). Additionally, neuronal loss was blunted within the CA3 hippocampal region of PNA5-treated αsyn mice. These data reveal that PNA5 treatment reduces cognitive dysfunction in a mouse model of PD. These changes are associated with decreased MIP-1β levels in plasma identifying a candidate biomarker for target engagement. Thus, PNA5 treatment could potentially fill the therapeutic gap for cognitive decline in PD.</p></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":4.6000,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The angiotensin (1–7) glycopeptide PNA5 improves cognition in a chronic progressive mouse model of Parkinson's disease through modulation of neuroinflammation\",\"authors\":\"\",\"doi\":\"10.1016/j.expneurol.2024.114926\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Cognitive decline in Parkinson's Disease (PD) is a prevalent and undertreated aspect of disease. Currently, no therapeutics adequately improve this aspect of disease. It has been previously shown that MAS receptor agonism via the glycosylated Angiotensin (1–7) peptide, PNA5, effectively reduces cognitive decline in models of vascular contributions to cognitive impairment and dementia (VCID). PNA5 has a brain/plasma ratio of 0.255 indicating good brain penetration. The goal of the present study was to determine if (1) systemic administration of PNA5 rescued cognitive decline in a mouse model of PD, and (2) if improvements in cognitive status could be correlated with changes to histopathological or blood plasma-based changes. Mice over-expressing human, wild-type α-synuclein (αSyn) under the Thy1 promoter (Thy1-αSyn mice, “line 61”) were used as a model of PD with cognitive decline. Thy1-αSyn mice were treated with a systemic dose of PNA5, or saline (1 mg/kg/day) beginning at 4 months of age and underwent behavioral testing at 6 months, compared to WT. Subsequently, mice brains were analyzed for changes to brain pathology, and blood plasma was examined with a Multiplex Immunoassay for peripheral cytokine changes. Treatment with PNA5 reversed cognitive dysfunction measured by Novel Object Recognition and spontaneous alteration in a Y-maze in Thy1-αSyn mice. PNA5 treatment was specific to cognitive deficits, as fine-motor disturbances were unchanged. Enhanced cognition was associated with decreases in hippocampal inflammation and reductions in circulating levels of Macrophage Induced Protein (MIP-1β). Additionally, neuronal loss was blunted within the CA3 hippocampal region of PNA5-treated αsyn mice. These data reveal that PNA5 treatment reduces cognitive dysfunction in a mouse model of PD. These changes are associated with decreased MIP-1β levels in plasma identifying a candidate biomarker for target engagement. Thus, PNA5 treatment could potentially fill the therapeutic gap for cognitive decline in PD.</p></div>\",\"PeriodicalId\":12246,\"journal\":{\"name\":\"Experimental Neurology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2024-08-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Experimental Neurology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0014488624002528\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental Neurology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0014488624002528","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
The angiotensin (1–7) glycopeptide PNA5 improves cognition in a chronic progressive mouse model of Parkinson's disease through modulation of neuroinflammation
Cognitive decline in Parkinson's Disease (PD) is a prevalent and undertreated aspect of disease. Currently, no therapeutics adequately improve this aspect of disease. It has been previously shown that MAS receptor agonism via the glycosylated Angiotensin (1–7) peptide, PNA5, effectively reduces cognitive decline in models of vascular contributions to cognitive impairment and dementia (VCID). PNA5 has a brain/plasma ratio of 0.255 indicating good brain penetration. The goal of the present study was to determine if (1) systemic administration of PNA5 rescued cognitive decline in a mouse model of PD, and (2) if improvements in cognitive status could be correlated with changes to histopathological or blood plasma-based changes. Mice over-expressing human, wild-type α-synuclein (αSyn) under the Thy1 promoter (Thy1-αSyn mice, “line 61”) were used as a model of PD with cognitive decline. Thy1-αSyn mice were treated with a systemic dose of PNA5, or saline (1 mg/kg/day) beginning at 4 months of age and underwent behavioral testing at 6 months, compared to WT. Subsequently, mice brains were analyzed for changes to brain pathology, and blood plasma was examined with a Multiplex Immunoassay for peripheral cytokine changes. Treatment with PNA5 reversed cognitive dysfunction measured by Novel Object Recognition and spontaneous alteration in a Y-maze in Thy1-αSyn mice. PNA5 treatment was specific to cognitive deficits, as fine-motor disturbances were unchanged. Enhanced cognition was associated with decreases in hippocampal inflammation and reductions in circulating levels of Macrophage Induced Protein (MIP-1β). Additionally, neuronal loss was blunted within the CA3 hippocampal region of PNA5-treated αsyn mice. These data reveal that PNA5 treatment reduces cognitive dysfunction in a mouse model of PD. These changes are associated with decreased MIP-1β levels in plasma identifying a candidate biomarker for target engagement. Thus, PNA5 treatment could potentially fill the therapeutic gap for cognitive decline in PD.
期刊介绍:
Experimental Neurology, a Journal of Neuroscience Research, publishes original research in neuroscience with a particular emphasis on novel findings in neural development, regeneration, plasticity and transplantation. The journal has focused on research concerning basic mechanisms underlying neurological disorders.