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Zhu A, Jiang Y, Pan L, Li J, Huang Y, Shi M, Di L, Wang L, Wang R. Cell inspired delivery system equipped with natural membrane structures in applications for rescuing ischemic stroke. J Control Release 2025; 377:54-80. [PMID: 39547421 DOI: 10.1016/j.jconrel.2024.11.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 10/10/2024] [Accepted: 11/07/2024] [Indexed: 11/17/2024]
Abstract
Ischemic stroke (IS), accounting for 87 % of stroke incidences, constitutes a paramount health challenge owing to neurological impairments and irreversible tissue damage arising from cerebral ischemia. Chief among therapeutic obstacles are the restrictive penetration of the blood-brain barrier (BBB) and insufficient targeting precision, hindering the accumulation of drugs in ischemic brain areas. Motivated by the remarkable capabilities of natural membrane-based delivery vehicles in achieving targeted delivery and traversing the BBB, thanks to their biocompatible architecture and bioactive components, numerous membrane-engineered systems such as cells, cell membranes and extracellular vesicles have emerged as promising platforms to augment IS treatment efficacy with the help of nanotechnology. This review consolidates the primary pathological manifestations following IS, elucidates the unique functionalities of natural membrane drug delivery systems (DDSs) with nanotechnology, as well as delineates the structural characteristics of various natural membranes alongside rational design strategies employed. The review illuminates both the potential and challenges encountered when employing natural membrane DDSs in IS drug therapy, offering fresh perspectives and insights for devising efficacious and practical delivery systems tailored to IS intervention.
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Affiliation(s)
- Anran Zhu
- School of Pharmacy, Jiangsu Provincial TCM Engineering Technology Research Center of High Efficient Drug Delivery System, Nanjing University of Chinese Medicine, Nanjing 210023, China; State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yingyu Jiang
- School of Pharmacy, Jiangsu Provincial TCM Engineering Technology Research Center of High Efficient Drug Delivery System, Nanjing University of Chinese Medicine, Nanjing 210023, China; State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Longxiang Pan
- School of Pharmacy, Jiangsu Provincial TCM Engineering Technology Research Center of High Efficient Drug Delivery System, Nanjing University of Chinese Medicine, Nanjing 210023, China; State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Jiale Li
- School of Pharmacy, Jiangsu Provincial TCM Engineering Technology Research Center of High Efficient Drug Delivery System, Nanjing University of Chinese Medicine, Nanjing 210023, China; State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yao Huang
- School of Pharmacy, Jiangsu Provincial TCM Engineering Technology Research Center of High Efficient Drug Delivery System, Nanjing University of Chinese Medicine, Nanjing 210023, China; State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Minghui Shi
- School of Pharmacy, Jiangsu Provincial TCM Engineering Technology Research Center of High Efficient Drug Delivery System, Nanjing University of Chinese Medicine, Nanjing 210023, China; State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Liuqing Di
- School of Pharmacy, Jiangsu Provincial TCM Engineering Technology Research Center of High Efficient Drug Delivery System, Nanjing University of Chinese Medicine, Nanjing 210023, China; State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Lei Wang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| | - Ruoning Wang
- School of Pharmacy, Jiangsu Provincial TCM Engineering Technology Research Center of High Efficient Drug Delivery System, Nanjing University of Chinese Medicine, Nanjing 210023, China; State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China.
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D'Egidio F, Castelli V, d'Angelo M, Ammannito F, Quintiliani M, Cimini A. Brain incoming call from glia during neuroinflammation: Roles of extracellular vesicles. Neurobiol Dis 2024; 201:106663. [PMID: 39251030 DOI: 10.1016/j.nbd.2024.106663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 09/04/2024] [Accepted: 09/06/2024] [Indexed: 09/11/2024] Open
Abstract
The functionality of the central nervous system (CNS) relies on the connection, integration, and the exchange of information among neural cells. The crosstalk among glial cells and neurons is pivotal for a series of neural functions, such as development of the nervous system, electric conduction, synaptic transmission, neural circuit establishment, and brain homeostasis. Glial cells are crucial players in the maintenance of brain functionality in physiological and disease conditions. Neuroinflammation is a common pathological process in various brain disorders, such as neurodegenerative diseases, and infections. Glial cells, including astrocytes, microglia, and oligodendrocytes, are the main mediators of neuroinflammation, as they can sense and respond to brain insults by releasing pro-inflammatory or anti-inflammatory factors. Recent evidence indicates that extracellular vesicles (EVs) are pivotal players in the intercellular communication that underlies physiological and pathological processes. In particular, glia-derived EVs play relevant roles in modulating neuroinflammation, either by promoting or inhibiting the activation of glial cells and neurons, or by facilitating the clearance or propagation of pathogenic proteins. The involvement of EVs in neurodegenerative diseases such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), and Multiple Sclerosis (MS)- which share hallmarks such as neuroinflammation and oxidative stress to DNA damage, alterations in neurotrophin levels, mitochondrial impairment, and altered protein dynamics- will be dissected, showing how EVs act as pivotal cell-cell mediators of toxic stimuli, thereby propagating degeneration and cell death signaling. Thus, this review focuses on the EVs secreted by microglia, astrocytes, oligodendrocytes and in neuroinflammatory conditions, emphasizing on their effects on neurons and on central nervous system functions, considering both their beneficial and detrimental effects.
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Affiliation(s)
- Francesco D'Egidio
- Department of Life, Health and Environmental Sciences, University of L'Aquila, Italy 67100, Via Vetoio - Coppito1, Building "Renato Ricamo"
| | - Vanessa Castelli
- Department of Life, Health and Environmental Sciences, University of L'Aquila, Italy 67100, Via Vetoio - Coppito1, Building "Renato Ricamo"
| | - Michele d'Angelo
- Department of Life, Health and Environmental Sciences, University of L'Aquila, Italy 67100, Via Vetoio - Coppito1, Building "Renato Ricamo".
| | - Fabrizio Ammannito
- Department of Life, Health and Environmental Sciences, University of L'Aquila, Italy 67100, Via Vetoio - Coppito1, Building "Renato Ricamo"
| | - Massimiliano Quintiliani
- Department of Life, Health and Environmental Sciences, University of L'Aquila, Italy 67100, Via Vetoio - Coppito1, Building "Renato Ricamo"
| | - Annamaria Cimini
- Department of Life, Health and Environmental Sciences, University of L'Aquila, Italy 67100, Via Vetoio - Coppito1, Building "Renato Ricamo"
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3
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Ryou MG, Burton S. Intermittent hypoxic training - derived exosomes in stroke rehabilitation. Front Integr Neurosci 2024; 18:1475234. [PMID: 39323911 PMCID: PMC11422222 DOI: 10.3389/fnint.2024.1475234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Accepted: 08/19/2024] [Indexed: 09/27/2024] Open
Abstract
Ischemic stroke is the fourth leading cause of adult disability in the US, and it is a huge social burden all over the world. However, the efficient treatment of ischemic stroke is not available. An apparent reason for failing to find or develop an intervention for ischemic stroke is contributed to the tight blood-brain barrier (BBB). The unique characteristics of exosomes that can traverse BBB have been highlighted among researchers investigating interventions for ischemic stroke conditions. Additionally, intermittent hypoxic training has been considered a potential intervention in the treatment or rehabilitation process of ischemic stroke patients. In this mini-review, we are going to review the possibility of applying exosomes produced by a subject who does intermittent hypoxic conditioning in a treatment program for ischemic stroke.
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Affiliation(s)
- Myoung-Gwi Ryou
- Department of Medical Laboratory Sciences, Public Health, and Nutrition Science, College of Health Science, Tarleton State University, Fort Worth, TX, United States
| | - Summer Burton
- Department of Medical Laboratory Sciences, Public Health, and Nutrition Science, College of Health Science, Tarleton State University, Fort Worth, TX, United States
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Xu H, Li H, Zhang P, Gao Y, Ma H, Gao T, Liu H, Hua W, Zhang L, Zhang X, Yang P, Liu J. The functions of exosomes targeting astrocytes and astrocyte-derived exosomes targeting other cell types. Neural Regen Res 2024; 19:1947-1953. [PMID: 38227520 PMCID: PMC11040311 DOI: 10.4103/1673-5374.390961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 07/20/2023] [Accepted: 09/08/2023] [Indexed: 01/17/2024] Open
Abstract
Astrocytes are the most abundant glial cells in the central nervous system; they participate in crucial biological processes, maintain brain structure, and regulate nervous system function. Exosomes are cell-derived extracellular vesicles containing various bioactive molecules including proteins, peptides, nucleotides, and lipids secreted from their cellular sources. Increasing evidence shows that exosomes participate in a communication network in the nervous system, in which astrocyte-derived exosomes play important roles. In this review, we have summarized the effects of exosomes targeting astrocytes and the astrocyte-derived exosomes targeting other cell types in the central nervous system. We also discuss the potential research directions of the exosome-based communication network in the nervous system. The exosome-based intercellular communication focused on astrocytes is of great significance to the biological and/or pathological processes in different conditions in the brain. New strategies may be developed for the diagnosis and treatment of neurological disorders by focusing on astrocytes as the central cells and utilizing exosomes as communication mediators.
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Affiliation(s)
- Hongye Xu
- Neurovascular Center, Changhai Hospital, Naval Medical University, Shanghai, China
| | - He Li
- Neurovascular Center, Changhai Hospital, Naval Medical University, Shanghai, China
- Department of Emergency, Naval Hospital of Eastern Theater, Zhoushan, Zhejiang Province, China
| | - Ping Zhang
- Neurovascular Center, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yuan Gao
- Neurovascular Center, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Hongyu Ma
- Neurovascular Center, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Tianxiang Gao
- Neurovascular Center, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Hanchen Liu
- Neurovascular Center, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Weilong Hua
- Neurovascular Center, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Lei Zhang
- Neurovascular Center, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Xiaoxi Zhang
- Neurovascular Center, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Pengfei Yang
- Neurovascular Center, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Jianmin Liu
- Neurovascular Center, Changhai Hospital, Naval Medical University, Shanghai, China
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5
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Yamamoto K, Scilabra SD, Bonelli S, Jensen A, Scavenius C, Enghild JJ, Strickland DK. Novel insights into the multifaceted and tissue-specific roles of the endocytic receptor LRP1. J Biol Chem 2024; 300:107521. [PMID: 38950861 PMCID: PMC11325810 DOI: 10.1016/j.jbc.2024.107521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 06/22/2024] [Accepted: 06/26/2024] [Indexed: 07/03/2024] Open
Abstract
Receptor-mediated endocytosis provides a mechanism for the selective uptake of specific molecules thereby controlling the composition of the extracellular environment and biological processes. The low-density lipoprotein receptor-related protein 1 (LRP1) is a widely expressed endocytic receptor that regulates cellular events by modulating the levels of numerous extracellular molecules via rapid endocytic removal. LRP1 also participates in signalling pathways through this modulation as well as in the interaction with membrane receptors and cytoplasmic adaptor proteins. LRP1 SNPs are associated with several diseases and conditions such as migraines, aortic aneurysms, cardiopulmonary dysfunction, corneal clouding, and bone dysmorphology and mineral density. Studies using Lrp1 KO mice revealed a critical, nonredundant and tissue-specific role of LRP1 in regulating various physiological events. However, exactly how LRP1 functions to regulate so many distinct and specific processes is still not fully clear. Our recent proteomics studies have identified more than 300 secreted proteins that either directly interact with LRP1 or are modulated by LRP1 in various tissues. This review will highlight the remarkable ability of this receptor to regulate secreted molecules in a tissue-specific manner and discuss potential mechanisms underpinning such specificity. Uncovering the depth of these "hidden" specific interactions modulated by LRP1 will provide novel insights into a dynamic and complex extracellular environment that is involved in diverse biological and pathological processes.
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Affiliation(s)
- Kazuhiro Yamamoto
- Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom.
| | - Simone D Scilabra
- Proteomics Group of Ri.MED Foundation, Research Department IRCCS ISMETT, Palermo, Italy
| | - Simone Bonelli
- Proteomics Group of Ri.MED Foundation, Research Department IRCCS ISMETT, Palermo, Italy; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy
| | - Anders Jensen
- Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Carsten Scavenius
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Jan J Enghild
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Dudley K Strickland
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland, USA
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6
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Ghosh S, Jana R, Jana S, Basu R, Chatterjee M, Ranawat N, Das Sarma J. Differential expression of cellular prion protein (PrP C) in mouse hepatitis virus induced neuroinflammation. J Neurovirol 2024; 30:215-228. [PMID: 38922550 DOI: 10.1007/s13365-024-01215-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 05/09/2024] [Accepted: 05/20/2024] [Indexed: 06/27/2024]
Abstract
The cellular prion protein (PrPC) is an extracellular cell membrane protein. Due to its diversified roles, a definite role of PrPC has been difficult to establish. During viral infection, PrPC has been reported to play a pleiotropic role. Here, we have attempted to envision the function of PrPC in the neurotropic m-CoV-MHV-RSA59-induced model of neuroinflammation in C57BL/6 mice. A significant upregulation of PrPC at protein and mRNA levels was evident in infected mouse brains during the acute phase of neuroinflammation. Furthermore, investigation of the effect of MHV-RSA59 infection on PrPC expression in specific neuronal, microglial, and astrocytoma cell lines, revealed a differential expression of prion protein during neuroinflammation. Additionally, siRNA-mediated downregulation of prnp transcripts reduced the expression of viral antigen and viral infectivity in these cell lines. Cumulatively, our results suggest that PrPC expression significantly increases during acute MHV-RSA59 infection and that PrPC also assists in viral infectivity and viral replication.
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Affiliation(s)
- Satavisha Ghosh
- Department of Biological Sciences, Indian Institute of Science Education and Research, Kolkata, Mohanpur, 741246, India
| | - Rishika Jana
- Department of Biological Sciences, Indian Institute of Science Education and Research, Kolkata, Mohanpur, 741246, India
| | - Soumen Jana
- Department of Biological Sciences, Indian Institute of Science Education and Research, Kolkata, Mohanpur, 741246, India
- Optical NeuroImaging Unit, Okinawa Institute of Science and Technology, Okinawa, Japan
| | - Rahul Basu
- Department of Biological Sciences, Indian Institute of Science Education and Research, Kolkata, Mohanpur, 741246, India
- Department of Biochemistry and Structural Biology, The University of Texas Health Science Center, San Antonio, TX, USA
| | - Madhurima Chatterjee
- Department of Biological Sciences, Indian Institute of Science Education and Research, Kolkata, Mohanpur, 741246, India
| | - Nishtha Ranawat
- Department of Biological Sciences, Indian Institute of Science Education and Research, Kolkata, Mohanpur, 741246, India
- Burke Neurological Institute, Weill Cornell Medicine, New York, NY, USA
| | - Jayasri Das Sarma
- Department of Biological Sciences, Indian Institute of Science Education and Research, Kolkata, Mohanpur, 741246, India.
- Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
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7
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Mantuano E, Zampieri C, Azmoon P, Gunner CB, Heye KR, Gonias SL. An LRP1-binding motif in cellular prion protein replicates cell-signaling activities of the full-length protein. JCI Insight 2023; 8:e170121. [PMID: 37368488 PMCID: PMC10445690 DOI: 10.1172/jci.insight.170121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 06/23/2023] [Indexed: 06/29/2023] Open
Abstract
Low-density lipoprotein receptor-related protein-1 (LRP1) functions as a receptor for nonpathogenic cellular prion protein (PrPC), which is released from cells by ADAM (a disintegrin and metalloproteinase domain) proteases or in extracellular vesicles. This interaction activates cell signaling and attenuates inflammatory responses. We screened 14-mer PrPC-derived peptides and identified a putative LRP1 recognition motif in the PrPC sequence spanning residues 98-111. A synthetic peptide (P3) corresponding to this region replicated the cell-signaling and biological activities of full-length shed PrPC. P3 blocked LPS-elicited cytokine expression in macrophages and microglia and rescued the heightened sensitivity to LPS in mice in which the PrPC gene (Prnp) had been deleted. P3 activated ERK1/2 and induced neurite outgrowth in PC12 cells. The response to P3 required LRP1 and the NMDA receptor and was blocked by the PrPC-specific antibody, POM2. P3 has Lys residues, which are typically necessary for LRP1 binding. Converting Lys100 and Lys103 into Ala eliminated the activity of P3, suggesting that these residues are essential in the LRP1-binding motif. A P3 derivative in which Lys105 and Lys109 were converted into Ala retained activity. We conclude that the biological activities of shed PrPC, attributed to interaction with LRP1, are retained in synthetic peptides, which may be templates for therapeutics development.
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8
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Li B, Ma Z, Li Z. A novel regulator in Alzheimer's disease progression: The astrocyte-derived extracellular vesicles. Ageing Res Rev 2023; 86:101871. [PMID: 36736378 DOI: 10.1016/j.arr.2023.101871] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 01/17/2023] [Accepted: 01/28/2023] [Indexed: 02/05/2023]
Abstract
Alzheimer's disease (AD) is known as an age-related irreversible neurodegenerative disease. AD seriously endangers the health of the elderly, but there is still no effective treatment. In the past several decades, the significant role of astrocytes in the process of AD has been universally acknowledged. In addition, extracellular vesicles (EVs) have been recognized as an essential mediator in intercellular communication and participate in various pathophysiological processes by carrying and transporting diverse cargoes. Moreover, specific conditions and stimuli can modulate the amount and properties of astrocyte-derived EVs (ADEVs) to affect AD progression. Thus, recent studies focused on the involvement of ADEVs in the pathogenesis of AD and the potential application of ADEVs in the diagnosis and treatment of AD, which provides a new direction and possibility for revealing the mystery of AD. Interestingly, it can be concluded that ADEVs have both pathogenic and protective effects in the process of AD through a comprehensive generalization. In this review, we aim to summarize the multi-faces of ADEVs effects on AD development, which can provide a novel strategy to investigate the underlying mechanism in AD. We also summarize the current ADEVs clinically relevant studies to raise the potential use of ADEVs in the discovery of novel biomarkers for diagnosis and therapeutic targets for AD.
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Affiliation(s)
- Biao Li
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China.; School of Medicine, Sun Yat-sen University, Shenzhen 518107, China
| | - Zhixin Ma
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China
| | - Zhigang Li
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China..
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9
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Oyarce K, Cepeda MY, Lagos R, Garrido C, Vega-Letter AM, Garcia-Robles M, Luz-Crawford P, Elizondo-Vega R. Neuroprotective and Neurotoxic Effects of Glial-Derived Exosomes. Front Cell Neurosci 2022; 16:920686. [PMID: 35813501 PMCID: PMC9257100 DOI: 10.3389/fncel.2022.920686] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 06/06/2022] [Indexed: 12/19/2022] Open
Abstract
Exosomes derived from glial cells such as astrocytes, microglia, and oligodendrocytes can modulate cell communication in the brain and exert protective or neurotoxic effects on neurons, depending on the environmental context upon their release. Their isolation, characterization, and analysis under different conditions in vitro, in animal models and samples derived from patients has allowed to define the participation of other molecular mechanisms behind neuroinflammation and neurodegeneration spreading, and to propose their use as a potential diagnostic tool. Moreover, the discovery of specific molecular cargos, such as cytokines, membrane-bound and soluble proteins (neurotrophic factors, growth factors, misfolded proteins), miRNA and long-non-coding RNA, that are enriched in glial-derived exosomes with neuroprotective or damaging effects, or their inhibitors can now be tested as therapeutic tools. In this review we summarize the state of the art on how exosomes secretion by glia can affect neurons and other glia from the central nervous system in the context of neurodegeneration and neuroinflammation, but also, on how specific stress stimuli and pathological conditions can change the levels of exosome secretion and their properties.
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Affiliation(s)
- Karina Oyarce
- Laboratorio de Neuroinmunología, Facultad de Medicina y Ciencia, Universidad San Sebastián, Concepción, Chile
| | - María Yamila Cepeda
- Laboratorio de Neuroinmunología, Facultad de Medicina y Ciencia, Universidad San Sebastián, Concepción, Chile
- Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Raúl Lagos
- Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Camila Garrido
- Laboratorio de Neuroinmunología, Facultad de Medicina y Ciencia, Universidad San Sebastián, Concepción, Chile
- Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Ana María Vega-Letter
- Facultad de Medicina, Centro de Investigación Biomédica, Universidad de los Andes, Santiago, Chile
| | - María Garcia-Robles
- Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Patricia Luz-Crawford
- Facultad de Medicina, Centro de Investigación Biomédica, Universidad de los Andes, Santiago, Chile
| | - Roberto Elizondo-Vega
- Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
- *Correspondence: Roberto Elizondo-Vega,
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10
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Mantuano E, Azmoon P, Banki MA, Sigurdson CJ, Campana WM, Gonias SL. A Soluble PrP C Derivative and Membrane-Anchored PrP C in Extracellular Vesicles Attenuate Innate Immunity by Engaging the NMDA-R/LRP1 Receptor Complex. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:85-96. [PMID: 34810220 PMCID: PMC8702456 DOI: 10.4049/jimmunol.2100412] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 10/19/2021] [Indexed: 01/03/2023]
Abstract
Nonpathogenic cellular prion protein (PrPC) demonstrates anti-inflammatory activity; however, the responsible mechanisms are incompletely defined. PrPC exists as a GPI-anchored membrane protein in diverse cells; however, PrPC may be released from cells by ADAM proteases or when packaged into extracellular vesicles (EVs). In this study, we show that a soluble derivative of PrPC (S-PrP) counteracts inflammatory responses triggered by pattern recognition receptors in macrophages, including TLR2, TLR4, TLR7, TLR9, NOD1, and NOD2. S-PrP also significantly attenuates the toxicity of LPS in mice. The response of macrophages to S-PrP is mediated by a receptor assembly that includes the N-methyl-d-aspartate receptor (NMDA-R) and low-density lipoprotein receptor-related protein-1 (LRP1). PrPC was identified in EVs isolated from human plasma. These EVs replicated the activity of S-PrP, inhibiting cytokine expression and IκBα phosphorylation in LPS-treated macrophages. The effects of plasma EVs on LPS-treated macrophages were blocked by PrPC-specific Ab, by antagonists of LRP1 and the NMDA-R, by deleting Lrp1 in macrophages, and by inhibiting Src family kinases. Phosphatidylinositol-specific phospholipase C dissociated the LPS-regulatory activity from EVs, rendering the EVs inactive as LPS inhibitors. The LPS-regulatory activity that was lost from phosphatidylinositol-specific phospholipase C-treated EVs was recovered in solution. Collectively, these results demonstrate that GPI-anchored PrPC is the essential EV component required for the observed immune regulatory activity of human plasma EVs. S-PrP and EV-associated PrPC regulate innate immunity by engaging the NMDA-R/LRP1 receptor system in macrophages. The scope of pattern recognition receptors antagonized by S-PrP suggests that released forms of PrPC may have broad anti-inflammatory activity.
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Affiliation(s)
| | - Pardis Azmoon
- Department of Pathology, University of California San Diego, La Jolla, CA
| | - Michael A Banki
- Department of Pathology, University of California San Diego, La Jolla, CA
| | | | - Wendy M Campana
- Department of Anesthesiology and Program in Neurosciences, University of California San Diego, La Jolla, CA; and
- Veterans Administration San Diego Healthcare System, San Diego, CA
| | - Steven L Gonias
- Department of Pathology, University of California San Diego, La Jolla, CA;
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11
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Zhang B, Yin X, Lang Y, Han X, Shao J, Bai R, Cui L. Role of cellular prion protein in splenic CD4 + T cell differentiation in cerebral ischaemic/reperfusion. Ann Clin Transl Neurol 2021; 8:2040-2051. [PMID: 34524735 PMCID: PMC8528449 DOI: 10.1002/acn3.51453] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 07/25/2021] [Accepted: 08/30/2021] [Indexed: 11/29/2022] Open
Abstract
Objective Cellular prion protein (PrPC), the primary form of prion diseases pathogen, has received increasing attention for its protective effect against ischaemic stroke. Little is known about its role in peripheral immune responses after cerebral ischaemia/reperfusion (I/R) injury. This study is to detect the variation of splenic CD4+ T lymphocytes differentiation and the concentration of inflammatory cytokines after murine cerebral I/R injury in the context of PRNP expression as well as its influence on the ischaemic neuronal apoptosis. Methods We established the cerebral ischaemic murine model of different PRNP genotypes. We detected the percentage of splenic CD4+PrPC+ T cells of PRNP wild‐type mice and the ratio of splenic Th1/2/17 lymphocytes of mice of different PRNP expression. The relevant inflammatory cytokines were then measured. Oxygen glucose deprivation/reperfusion (OGD/R) HT22 mouse hippocampal neurons were co‐cultured with the T‐cell‐conditioned medium harvested from the spleen of modelled mice and then the neuronal apoptosis was detected. Results CD4+ PrPC+ T lymphocytes in wild‐type mice elevated after MCAO/R. PRNP expression deficiency led to an elevation of Th1/17 phenotypes and the promotion of pro‐inflammatory cytokines, while PRNP overexpression led to the elevation of Th2 phenotype and upregulation of anti‐inflammatory cytokines. In addition, PrPC‐overexpressed CD4+T cells weakened the apoptosis of OGD/R HT‐22 murine hippocampal neurons caused by MCAO/R CD4+ T‐cell‐conditioned medium, while PrPC deficiency enhanced apoptosis. Interpretation PrPC works as a neuron protector in the CNS when I/R injury occurs and affects the peripheral immune responses and defends against stroke‐induced neuronal apoptosis.
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Affiliation(s)
- Baizhuo Zhang
- Department of Neurology, Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Xiang Yin
- Department of Neurology, Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Yue Lang
- Department of Neurology, Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Xiaoou Han
- Department of Neurology, Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Jie Shao
- Department of Neurology, Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Rongrong Bai
- Department of Neurology, Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Li Cui
- Department of Neurology, Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, China
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12
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Dexter E, Kong Q. Neuroprotective effect and potential of cellular prion protein and its cleavage products for treatment of neurodegenerative disorders part II: strategies for therapeutics development. Expert Rev Neurother 2021; 21:983-991. [PMID: 34470554 DOI: 10.1080/14737175.2021.1965882] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Introduction: The cellular prion protein (PrPC), some of its derivatives (especially PrP N-terminal N1 peptide and shed PrP), and PrPC-containing exosomes have strong neuroprotective activities, which have been reviewed in the companion article (Part I) and are briefly summarized here.Areas covered: We propose that elevating the extracellular levels of a protective PrP form using gene therapy and other approaches is a very promising novel avenue for prophylactic and therapeutic treatments against prion disease, Alzheimer's disease, and several other neurodegenerative diseases. We will dissect the pros and cons of various potential PrP-based treatment options and propose a few strategies that are more likely to succeed. The cited references were obtained from extensive PubMed searches of recent literature, including peer-reviewed original articles and review articles.Expert opinion: Concurrent knockdown of celllular PrP expression and elevation of the extracellular levels of a neuroprotective PrP N-terminal peptide via optimized gene therapy vectors is a highly promising broad-spectrum prophylactic and therapeutic strategy against several neurodegenerative diseases, including prion diseases, Alzheimer's disease and Parkinson's disease.
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Affiliation(s)
- Emily Dexter
- Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Qingzhong Kong
- Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.,Department of Neurology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
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13
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Yaghoubi S, Najminejad H, Dabaghian M, Karimi MH, Abdollahpour-Alitappeh M, Rad F, Mahi-Birjand M, Mohammadi S, Mohseni F, Sobhani Lari M, Teymouri GH, Rigi Yousofabadi E, Salmani A, Bagheri N. How hypoxia regulate exosomes in ischemic diseases and cancer microenvironment? IUBMB Life 2020; 72:1286-1305. [PMID: 32196941 DOI: 10.1002/iub.2275] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 03/08/2020] [Indexed: 12/14/2022]
Abstract
Exosomes, as natural occurring vesicles, play highly important roles in the behavior and fate of ischemic diseases and different tumors. Secretion, composition, and function of exosomes are remarkably influenced by hypoxia in ischemic diseases and tumor microenvironment. Exosomes secreted from hypoxic cells affect development, growth, angiogenesis, and progression in ischemic diseases and tumors through a variety of signaling pathways. In this review article, we discuss how hypoxia affects the quantity and quality of exosomes, and review the mechanisms by which hypoxic cell-derived exosomes regulate ischemic cell behaviors in both cancerous and noncancerous cells.
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Affiliation(s)
- Sajad Yaghoubi
- Department of Clinical Microbiology, Iranshahr University of Medical Sciences, Iranshahr, Iran
| | - Hamid Najminejad
- Department of Medical Genetics, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mehran Dabaghian
- Research and Development Department, Razi Vaccine and Serum Research Institute, Agricultural Research Education and Extension Organization (AREEO), Karaj, Iran
| | | | | | - Fariba Rad
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Motahareh Mahi-Birjand
- Infectious Disease Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Shiva Mohammadi
- Department of Biotechnology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | | | - Mohammad Sobhani Lari
- Cellular and Molecular Biology Research Center, Larestan University of Medical Sciences, Larestan, Iran
| | | | | | | | - Nader Bagheri
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
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14
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The diabetes pandemic and associated infections: suggestions for clinical microbiology. ACTA ACUST UNITED AC 2018; 30:1-17. [PMID: 30662163 PMCID: PMC6319590 DOI: 10.1097/mrm.0000000000000155] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 10/08/2017] [Indexed: 12/15/2022]
Abstract
There are 425 million people with diabetes mellitus in the world. By 2045, this figure will grow to over 600 million. Diabetes mellitus is classified among noncommunicable diseases. Evidence points to a key role of microbes in diabetes mellitus, both as infectious agents associated with the diabetic status and as possible causative factors of diabetes mellitus. This review takes into account the different forms of diabetes mellitus, the genetic determinants that predispose to type 1 and type 2 diabetes mellitus (especially those with possible immunologic impact), the immune dysfunctions that have been documented in diabetes mellitus. Common infections occurring more frequently in diabetic vs. nondiabetic individuals are reviewed. Infectious agents that are suspected of playing an etiologic/triggering role in diabetes mellitus are presented, with emphasis on enteroviruses, the hygiene hypothesis, and the environment. Among biological agents possibly linked to diabetes mellitus, the gut microbiome, hepatitis C virus, and prion-like protein aggregates are discussed. Finally, preventive vaccines recommended in the management of diabetic patients are considered, including the bacillus calmette-Guerin vaccine that is being tested for type 1 diabetes mellitus. Evidence supports the notion that attenuation of immune defenses (both congenital and secondary to metabolic disturbances as well as to microangiopathy and neuropathy) makes diabetic people more prone to certain infections. Attentive microbiologic monitoring of diabetic patients is thus recommendable. As genetic predisposition cannot be changed, research needs to identify the biological agents that may have an etiologic role in diabetes mellitus, and to envisage curative and preventive ways to limit the diabetes pandemic.
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15
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Bourgognon JM, Spiers JG, Scheiblich H, Antonov A, Bradley SJ, Tobin AB, Steinert JR. Alterations in neuronal metabolism contribute to the pathogenesis of prion disease. Cell Death Differ 2018; 25:1408-1425. [PMID: 29915278 DOI: 10.1038/s41418-018-0148-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 05/14/2018] [Accepted: 06/04/2018] [Indexed: 02/07/2023] Open
Abstract
Neurodegenerative conditions are characterised by a progressive loss of neurons, which is believed to be initiated by misfolded protein aggregations. During this time period, many physiological and metabolomic alterations and changes in gene expression contribute to the decline in neuronal function. However, these pathological effects have not been fully characterised. In this study, we utilised a metabolomic approach to investigate the metabolic changes occurring in the hippocampus and cortex of mice infected with misfolded prion protein. In order to identify these changes, the samples were analysed by ultrahigh-performance liquid chromatography-tandem mass spectroscopy. The present dataset comprises a total of 498 compounds of known identity, named biochemicals, which have undergone principal component analysis and supervised machine learning. The results generated are consistent with the prion-inoculated mice having significantly altered metabolic profiles. In particular, we highlight the alterations associated with the metabolism of glucose, neuropeptides, fatty acids, L-arginine/nitric oxide and prostaglandins, all of which undergo significant changes during the disease. These data provide possibilities for future studies targeting and investigating specific pathways to better understand the processes involved in neuronal dysfunction in neurodegenerative diseases.
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Affiliation(s)
| | - Jereme G Spiers
- MRC Toxicology Unit, University of Leicester, Lancaster Road, Leicester, LE1 9HN, UK
| | - Hannah Scheiblich
- MRC Toxicology Unit, University of Leicester, Lancaster Road, Leicester, LE1 9HN, UK
| | - Alexey Antonov
- MRC Toxicology Unit, University of Leicester, Lancaster Road, Leicester, LE1 9HN, UK
| | - Sophie J Bradley
- Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, G12 8QQ, UK
| | - Andrew B Tobin
- Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, G12 8QQ, UK
| | - Joern R Steinert
- MRC Toxicology Unit, University of Leicester, Lancaster Road, Leicester, LE1 9HN, UK.
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16
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Abstract
Several studies have indicated that certain misfolded amyloids composed of tau, β-amyloid or α-synuclein can be transferred from cell to cell, suggesting the contribution of mechanisms reminiscent of those by which infective prions spread through the brain. This process of a 'prion-like' spreading between cells is also relevant as a novel putative therapeutic target that could block the spreading of proteinaceous aggregates throughout the brain which may underlie the progressive nature of neurodegenerative diseases. The relevance of β-amyloid oligomers and cellular prion protein (PrPC) binding has been a focus of interest in Alzheimer's disease (AD). At the molecular level, β-amyloid/PrPC interaction takes place in two differently charged clusters of PrPC. In addition to β-amyloid, participation of PrPC in α-synuclein binding and brain spreading also appears to be relevant in α-synucleopathies. This review summarizes current knowledge about PrPC as a putative receptor for amyloid proteins and the physiological consequences of these interactions.
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Affiliation(s)
- José A Del Río
- Molecular and Cellular Neurobiotechnology, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Barcelona, Spain; Department of Cell Biology, Physiology and Immunology, University of Barcelona, Barcelona, Spain; Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain; Institute of Neuroscience, University of Barcelona, Barcelona, Spain.
| | - Isidre Ferrer
- Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain; Institute of Neuroscience, University of Barcelona, Barcelona, Spain; Department of Pathology and Experimental Therapeutics, University of Barcelona, Hospitalet de Llobregat, Spain; Senior Consultant Neuropathology, Service of Pathology, Bellvitge University Hospital, Hospitalet de Llobregat, Spain.
| | - Rosalina Gavín
- Molecular and Cellular Neurobiotechnology, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Barcelona, Spain; Department of Cell Biology, Physiology and Immunology, University of Barcelona, Barcelona, Spain; Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain; Institute of Neuroscience, University of Barcelona, Barcelona, Spain
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17
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Abstract
Currently all prion diseases are without effective treatment and are universally fatal. It is increasingly being recognized that the pathogenesis of many neurodegenerative diseases, such as Alzheimer disease (AD), includes "prion-like" properties. Hence, any effective therapeutic intervention for prion disease could have significant implications for other neurodegenerative diseases. Conversely, therapies that are effective in AD might also be therapeutically beneficial for prion disease. AD-like prion disease has no effective therapy. However, various vaccine and immunomodulatory approaches have shown great success in animal models of AD, with numerous ongoing clinical trials of these potential immunotherapies. More limited evidence suggests that immunotherapies may be effective in prion models and in naturally occurring prion disease. In particular, experimental data suggest that mucosal vaccination against prions can be effective for protection against orally acquired prion infection. Many prion diseases, including natural sheep scrapie, bovine spongiform encephalopathy, chronic wasting disease, and variant Creutzfeldt-Jakob disease, are thought to be acquired peripherally, mainly by oral exposure. Mucosal vaccination would be most applicable to this form of transmission. In this chapter we review various immunologically based strategies which are under development for prion infection.
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Affiliation(s)
- Thomas Wisniewski
- Center for Cognitive Neurology, New York University School of Medicine, New York, NY, United States; Department of Neurology, New York University School of Medicine, New York, NY, United States; Department of Pathology, New York University School of Medicine, New York, NY, United States; Department of Psychiatry, New York University School of Medicine, New York, NY, United States.
| | - Fernando Goñi
- Center for Cognitive Neurology, New York University School of Medicine, New York, NY, United States; Department of Neurology, New York University School of Medicine, New York, NY, United States
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18
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Lathe R, Darlix JL. Prion Protein PRNP: A New Player in Innate Immunity? The Aβ Connection. J Alzheimers Dis Rep 2017; 1:263-275. [PMID: 30480243 PMCID: PMC6159716 DOI: 10.3233/adr-170037] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/11/2017] [Indexed: 12/25/2022] Open
Abstract
The prion protein PRNP has been centrally implicated in the transmissible spongiform encephalopathies (TSEs), but its normal physiological role remains obscure. We highlight emerging evidence that PRNP displays antimicrobial activity, inhibiting the replication of multiple viruses, and also interacts directly with Alzheimer's disease (AD) amyloid-β (Aβ) peptide whose own antimicrobial role is now increasingly secure. PRNP and Aβ share share membrane-penetrating, nucleic acid binding, and antiviral properties with classical antimicrobial peptides such as LL-37. We discuss findings that binding of abnormal nucleic acids to PRNP leads to oligomerization of the protein, and suggest that this may be an entrapment and sequestration process that contributes to its antimicrobial activity. Some antimicrobial peptides are known to be exploited by infectious agents, and we cover evidence that PRNP is usurped by herpes simplex virus (HSV-1) that has evolved a virus-encoded 'anti-PRNP'.unction. These findings suggest that PRNP, like LL-37 and Aβ, is likely to be a component of the innate immune system, with implications for the pathoetiology of both AD and TSE.
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Affiliation(s)
- Richard Lathe
- Division of Infection and Pathway Medicine, University of Edinburgh, Edinburgh, UK
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Pushchino, Moscow Region, Russia
| | - Jean-Luc Darlix
- Faculté de Pharmacie, Centre Nationale de la Recherche Scientifique (CNRS) Unité 7213, Université de Strasbourg, Illkirch, France
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19
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Xavier-Elsas P, Ferreira RN, Gaspar-Elsas MIC. Surgical and immune reconstitution murine models in bone marrow research: Potential for exploring mechanisms in sepsis, trauma and allergy. World J Exp Med 2017; 7:58-77. [PMID: 28890868 PMCID: PMC5571450 DOI: 10.5493/wjem.v7.i3.58] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Revised: 06/11/2017] [Accepted: 06/30/2017] [Indexed: 02/06/2023] Open
Abstract
Bone marrow, the vital organ which maintains lifelong hemopoiesis, currently receives considerable attention, as a source of multiple cell types which may play important roles in repair at distant sites. This emerging function, distinct from, but closely related to, bone marrow roles in innate immunity and inflammation, has been characterized through a number of strategies. However, the use of surgical models in this endeavour has hitherto been limited. Surgical strategies allow the experimenter to predetermine the site, timing, severity and invasiveness of injury; to add or remove aggravating factors (such as infection and defects in immunity) in controlled ways; and to manipulate the context of repair, including reconstitution with selected immune cell subpopulations. This endows surgical models overall with great potential for exploring bone marrow responses to injury, inflammation and infection, and its roles in repair and regeneration. We review three different murine surgical models, which variously combine trauma with infection, antigenic stimulation, or immune reconstitution, thereby illuminating different aspects of the bone marrow response to systemic injury in sepsis, trauma and allergy. They are: (1) cecal ligation and puncture, a versatile model of polymicrobial sepsis; (2) egg white implant, an intriguing model of eosinophilia induced by a combination of trauma and sensitization to insoluble allergen; and (3) ectopic lung tissue transplantation, which allows us to dissect afferent and efferent mechanisms leading to accumulation of hemopoietic cells in the lungs. These models highlight the gain in analytical power provided by the association of surgical and immunological strategies.
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20
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Elezgarai SR, Biasini E. Common therapeutic strategies for prion and Alzheimer's diseases. Biol Chem 2017; 397:1115-1124. [PMID: 27279060 DOI: 10.1515/hsz-2016-0190] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Accepted: 06/03/2016] [Indexed: 01/19/2023]
Abstract
A number of unexpected pathophysiological connections linking different neurodegenerative diseases have emerged over the past decade. An example is provided by prion and Alzheimer's diseases. Despite being distinct pathologies, these disorders share several neurotoxic mechanisms, including accumulation of misfolded protein isoforms, stress of the protein synthesis machinery, and activation of a neurotoxic signaling mediated by the cellular prion protein. Here, in addition to reviewing these mechanisms, we will discuss the potential therapeutic interventions for prion and Alzheimer's diseases that are arising from the comprehension of their common neurodegenerative pathways.
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21
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Linden R. The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules. Front Mol Neurosci 2017; 10:77. [PMID: 28373833 PMCID: PMC5357658 DOI: 10.3389/fnmol.2017.00077] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2016] [Accepted: 03/06/2017] [Indexed: 12/18/2022] Open
Abstract
The prion glycoprotein (PrPC) is mostly located at the cell surface, tethered to the plasma membrane through a glycosyl-phosphatydil inositol (GPI) anchor. Misfolding of PrPC is associated with the transmissible spongiform encephalopathies (TSEs), whereas its normal conformer serves as a receptor for oligomers of the β-amyloid peptide, which play a major role in the pathogenesis of Alzheimer’s Disease (AD). PrPC is highly expressed in both the nervous and immune systems, as well as in other organs, but its functions are controversial. Extensive experimental work disclosed multiple physiological roles of PrPC at the molecular, cellular and systemic levels, affecting the homeostasis of copper, neuroprotection, stem cell renewal and memory mechanisms, among others. Often each such process has been heralded as the bona fide function of PrPC, despite restricted attention paid to a selected phenotypic trait, associated with either modulation of gene expression or to the engagement of PrPC with a single ligand. In contrast, the GPI-anchored prion protein was shown to bind several extracellular and transmembrane ligands, which are required to endow that protein with the ability to play various roles in transmembrane signal transduction. In addition, differing sets of those ligands are available in cell type- and context-dependent scenarios. To account for such properties, we proposed that PrPC serves as a dynamic platform for the assembly of signaling modules at the cell surface, with widespread consequences for both physiology and behavior. The current review advances the hypothesis that the biological function of the prion protein is that of a cell surface scaffold protein, based on the striking similarities of its functional properties with those of scaffold proteins involved in the organization of intracellular signal transduction pathways. Those properties are: the ability to recruit spatially restricted sets of binding molecules involved in specific signaling; mediation of the crosstalk of signaling pathways; reciprocal allosteric regulation with binding partners; compartmentalized responses; dependence of signaling properties upon posttranslational modification; and stoichiometric requirements and/or oligomerization-dependent impact on signaling. The scaffold concept may contribute to novel approaches to the development of effective treatments to hitherto incurable neurodegenerative diseases, through informed modulation of prion protein-ligand interactions.
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Affiliation(s)
- Rafael Linden
- Laboratory of Neurogenesis, Institute of Biophysics, Federal University of Rio de Janeiro Rio de Janeiro, Brazil
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22
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ONODERA T. Dual role of cellular prion protein in normal host and Alzheimer's disease. PROCEEDINGS OF THE JAPAN ACADEMY. SERIES B, PHYSICAL AND BIOLOGICAL SCIENCES 2017; 93:155-173. [PMID: 28413194 PMCID: PMC5489426 DOI: 10.2183/pjab.93.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Accepted: 01/26/2017] [Indexed: 06/07/2023]
Abstract
Using PrPC-knockout cell lines, it has been shown that the inhibition of apoptosis through STI1 is mediated by PrPC-dependent SOD activation. Antioxidant PrPC may contribute to suppression of inflammasome activation. PrPC is functionally involved in copper metabolism, signal transduction, neuroprotection, and cell maturation. Recently several reports have shown that PrPC participates in trans-membrane signaling processes associated with hematopoietic stem cell replication and neuronal differentiation. In another role, PrPC also tends to function as a neurotoxic protein. Aβ oligomer, which is associated with neurodegeneration in Alzheimer's disease (AD), has also been reported to act as a ligand of PrPC. However, the physiological role of PrPC as an Aβ42-binding protein is not clear. Actually, PrPC is critical in Aβ42-mediated autophagy in neurons. PrPC shows a beneficial role in lipid rafts to promote autophagy. Further search for PrPC-interaction molecules using Prnp-/- mice and various types of Prnp-/- cell lines under various conditions may elucidate other important PrPC important functions.
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Affiliation(s)
- Takashi ONODERA
- Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, the University of Tokyo, Tokyo, Japan
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23
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Yoon YM, Lee JH, Yun SP, Han YS, Yun CW, Lee HJ, Noh H, Lee SJ, Han HJ, Lee SH. Tauroursodeoxycholic acid reduces ER stress by regulating of Akt-dependent cellular prion protein. Sci Rep 2016; 6:39838. [PMID: 28004805 PMCID: PMC5177936 DOI: 10.1038/srep39838] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Accepted: 11/28/2016] [Indexed: 11/09/2022] Open
Abstract
Although mesenchymal stem cells (MSCs) are a promising cell source for regenerative medicine, ischemia-induced endoplasmic reticulum (ER) stress induces low MSC engraftment and limits their therapeutic efficacy. To overcome this, we investigated the protective effect of tauroursodeoxycholic acid (TUDCA), a bile acid, on ER stress in MSCs in vitro and in vivo. In ER stress conditions, TUDCA treatment of MSCs reduced the activation of ER stress-associated proteins, including GRP78, PERK, eIF2α, ATF4, IRE1α, JNK, p38, and CHOP. In particular, TUDCA inhibited the dissociation between GRP78 and PERK, resulting in reduced ER stress-mediated cell death. Next, to explore the ER stress protective mechanism induced by TUDCA treatment, TUDCA-mediated cellular prion protein (PrPC) activation was assessed. TUDCA treatment increased PrPC expression, which was regulated by Akt phosphorylation. Manganese-dependent superoxide dismutase (MnSOD) expression also increased significantly in response to signaling through the TUDCA-Akt axis. In a murine hindlimb ischemia model, TUDCA-treated MSC transplantation augmented the blood perfusion ratio, vessel formation, and transplanted cell survival more than untreated MSC transplantation did. Augmented functional recovery following MSC transplantation was blocked by PrPC downregulation. This study is the first to demonstrate that TUDCA protects MSCs against ER stress via Akt-dependent PrPC and Akt-MnSOD pathway.
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Affiliation(s)
- Yeo Min Yoon
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea
| | - Jun Hee Lee
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA
| | - Seung Pil Yun
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, USA
| | - Yong-Seok Han
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea
| | - Chul Won Yun
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea
| | - Hyun Jik Lee
- Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, and BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul 151-741, Republic of Korea
| | - Hyunjin Noh
- Department of Internal Medicine, Hyonam Kidney Laboratory, Soonchunhyang University, Seoul, Republic of Korea
| | - Sei-Jung Lee
- Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, and BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul 151-741, Republic of Korea
| | - Ho Jae Han
- Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, and BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul 151-741, Republic of Korea
| | - Sang Hun Lee
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea.,Departments of Biochemistry, Soonchunhyang University College of Medicine, Cheonan, 330-930, Republic of Korea
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Peggion C, Bertoli A, Sorgato MC. Almost a century of prion protein(s): From pathology to physiology, and back to pathology. Biochem Biophys Res Commun 2016; 483:1148-1155. [PMID: 27581199 DOI: 10.1016/j.bbrc.2016.07.118] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Accepted: 07/27/2016] [Indexed: 12/30/2022]
Abstract
Prions are one of the few pathogens whose name is renowned at all population levels, after the dramatic years pervaded by the fear of eating prion-infected food. If now this, somehow irrational, scare of bovine meat inexorably transmitting devastating brain disorders is largely subdued, several prion-related issues are still unsolved, precluding the design of therapeutic approaches that could slow, if not halt, prion diseases. One unsolved issue is, for example, the role of the prion protein (PrPC), whole conformational misfolding originates the prion but whose physiologic reason d'etre in neurons, and in cells at large, remains enigmatic. Preceded by a historical outline, the present review will discuss the functional pleiotropicity ascribed to PrPC, and whether this aspect could fall, at least in part, into a more concise framework. It will also be devoted to radically different perspectives for PrPC, which have been recently brought to the attention of the scientific world with unexpected force. Finally, it will discuss the possible reasons allowing an evolutionary conserved and benign protein, as PrPC is, to turn into a high affinity receptor for pathologic misfolded oligomers, and to transmit their toxic message into neurons.
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Affiliation(s)
- Caterina Peggion
- Department of Biomedical Sciences, University of Padova, Via Bassi 58/B, 35131 Padova, Italy.
| | - Alessandro Bertoli
- Department of Biomedical Sciences, University of Padova, Via Bassi 58/B, 35131 Padova, Italy
| | - M Catia Sorgato
- Department of Biomedical Sciences, University of Padova, Via Bassi 58/B, 35131 Padova, Italy; C.N.R. Institute of Neuroscience, University of Padova, Via Bassi 58/B, 35131 Padova, Italy.
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Yano M, Sakakibara R, Tateno F, Takahashi O, Nakamura H, Sugiyama M, Fang-Ching L, Kamijima S, Kamiya N, Suzuki H. Urodynamic findings in patients with Creutzfeldt-Jakob disease: a case report. Int Urol Nephrol 2016; 48:1579-83. [PMID: 27314246 DOI: 10.1007/s11255-016-1344-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Accepted: 06/10/2016] [Indexed: 02/04/2023]
Abstract
AIM OF STUDY Urinary dysfunction in Creutzfeldt-Jakob disease (CJD) patients is attributed to functional incontinence, since they often have immobility and loss of motivation. In contrast, previously no urodynamic findings are available in CJD patients. CASE REPORT We had 2 CJD patients who had urinary frequency and urinary retention. We performed urodynamics with the spouse's informed consent in order to explore the mechanism of urinary dysfunction in those cases. Case 1 had typical acute cognitive deterioration with incontinence and urinary retention, while case 2 had subacute cognitive deterioration (that started after admission) and nocturia. The urodynamic findings were diverse. One feature was detrusor overactivity during bladder filling in case 1. Another feature of urodynamic finding includes neurogenic change of sphincter EMG in case 1 and decreased bladder sensation in case 2. CONCLUSION Urodynamics in our two CJD patients revealed detrusor overactivity and neurogenic sphincter electromyogram, presumably reflecting pathological lesions in the prefrontal cortex/basal ganglia as well as the sacral spinal cord in CJD.
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Affiliation(s)
- Masashi Yano
- Urology, Toho University Sakura Medical Center, Sakura, Japan
| | - Ryuji Sakakibara
- Neurology, Internal Medicine, Toho University Sakura Medical Center, 564-1 Shimoshizu, Sakura, 285-8741, Japan.
| | - Fuyuki Tateno
- Neurology, Internal Medicine, Toho University Sakura Medical Center, 564-1 Shimoshizu, Sakura, 285-8741, Japan
| | - Osamu Takahashi
- Clinical Physiology Unit, Toho University Sakura Medical Center, Sakura, Japan
| | - Haruka Nakamura
- Clinical Physiology Unit, Toho University Sakura Medical Center, Sakura, Japan
| | - Megumi Sugiyama
- Clinical Physiology Unit, Toho University Sakura Medical Center, Sakura, Japan
| | - Lee Fang-Ching
- Urology, Toho University Sakura Medical Center, Sakura, Japan
| | | | - Naoto Kamiya
- Urology, Toho University Sakura Medical Center, Sakura, Japan
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Guitart K, Loers G, Buck F, Bork U, Schachner M, Kleene R. Improvement of neuronal cell survival by astrocyte-derived exosomes under hypoxic and ischemic conditions depends on prion protein. Glia 2016; 64:896-910. [PMID: 26992135 DOI: 10.1002/glia.22963] [Citation(s) in RCA: 97] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Accepted: 12/18/2015] [Indexed: 02/05/2023]
Abstract
Prion protein (PrP) protects neural cells against oxidative stress, hypoxia, ischemia, and hypoglycemia. In the present study we confirm that cultured PrP-deficient neurons are more sensitive to oxidative stress than wild-type neurons and present the novel findings that wild-type, but not PrP-deficient astrocytes protect wild-type cerebellar neurons against oxidative stress and that exosomes released from stressed wild-type, but not from stressed PrP-deficient astrocytes reduce neuronal cell death induced by oxidative stress. We show that neuroprotection by exosomes of stressed astrocytes depends on exosomal PrP but not on neuronal PrP and that astrocyte-derived exosomal PrP enters into neurons, suggesting neuronal uptake of astrocyte-derived exosomes. Upon exposure of wild-type astrocytes to hypoxic or ischemic conditions PrP levels in exosomes were increased. By mass spectrometry and Western blot analysis, we detected increased levels of 37/67 kDa laminin receptor, apolipoprotein E and the ribosomal proteins S3 and P0, and decreased levels of clusterin/apolipoprotein J in exosomes from wild-type astrocytes exposed to oxygen/glucose deprivation relative to exosomes from astrocytes maintained under normoxic conditions. The levels of these proteins were not altered in exosomes from stressed PrP-deficient astrocytes relative to unstressed PrP-deficient astrocytes. These results indicate that PrP in astrocytes is a sensor for oxidative stress and mediates beneficial cellular responses, e.g. release of exosomes carrying PrP and other molecules, resulting in improved survival of neurons under hypoxic and ischemic conditions.
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Affiliation(s)
- Kathrin Guitart
- Zentrum Für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
| | - Gabriele Loers
- Zentrum Für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
| | - Friedrich Buck
- Institut Für Klinische Chemie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
| | - Ute Bork
- Zentrum Für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
| | - Melitta Schachner
- Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey
- Center for Neuroscience, Shantou University Medical College, Shantou, Guangdong, China
| | - Ralf Kleene
- Zentrum Für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
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Luceri C, Bigagli E, Pitozzi V, Giovannelli L. A nutrigenomics approach for the study of anti-aging interventions: olive oil phenols and the modulation of gene and microRNA expression profiles in mouse brain. Eur J Nutr 2015; 56:865-877. [DOI: 10.1007/s00394-015-1134-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Accepted: 12/11/2015] [Indexed: 12/21/2022]
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Bakkebø MK, Mouillet-Richard S, Espenes A, Goldmann W, Tatzelt J, Tranulis MA. The Cellular Prion Protein: A Player in Immunological Quiescence. Front Immunol 2015; 6:450. [PMID: 26388873 PMCID: PMC4557099 DOI: 10.3389/fimmu.2015.00450] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Accepted: 08/19/2015] [Indexed: 01/09/2023] Open
Abstract
Despite intensive studies since the 1990s, the physiological role of the cellular prion protein (PrP(C)) remains elusive. Here, we present a novel concept suggesting that PrP(C) contributes to immunological quiescence in addition to cell protection. PrP(C) is highly expressed in diverse organs that by multiple means are particularly protected from inflammation, such as the brain, eye, placenta, pregnant uterus, and testes, while at the same time it is expressed in most cells of the lymphoreticular system. In this paradigm, PrP(C) serves two principal roles: to modulate the inflammatory potential of immune cells and to protect vulnerable parenchymal cells against noxious insults generated through inflammation. Here, we review studies of PrP(C) physiology in view of this concept.
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Affiliation(s)
- Maren K. Bakkebø
- Department of Basic Sciences and Aquatic Medicine, Faculty of Veterinary Medicine and Biosciences, Norwegian University of Life Sciences, Oslo, Norway
| | | | - Arild Espenes
- Department of Basic Sciences and Aquatic Medicine, Faculty of Veterinary Medicine and Biosciences, Norwegian University of Life Sciences, Oslo, Norway
| | - Wilfred Goldmann
- The Roslin Institute, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, UK
| | - Jörg Tatzelt
- Biochemistry of Neurodegenerative Diseases, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Bochum, Germany
| | - Michael A. Tranulis
- Department of Basic Sciences and Aquatic Medicine, Faculty of Veterinary Medicine and Biosciences, Norwegian University of Life Sciences, Oslo, Norway,*Correspondence: Michael A. Tranulis, Department of Basic Sciences and Aquatic Medicine, Faculty of Veterinary Medicine and Biosciences, Norwegian University of Life Sciences, Campus Adamstuen, Oslo 0033, Norway,
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Beckman D, Santos LE, Americo TA, Ledo JH, de Mello FG, Linden R. Prion Protein Modulates Monoaminergic Systems and Depressive-like Behavior in Mice. J Biol Chem 2015; 290:20488-98. [PMID: 26152722 DOI: 10.1074/jbc.m115.666156] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Indexed: 12/14/2022] Open
Abstract
We sought to examine interactions of the prion protein (PrP(C)) with monoaminergic systems due to: the role of PrP(C) in both Prion and Alzheimer diseases, which include clinical depression among their symptoms, the implication of monoamines in depression, and the hypothesis that PrP(C) serves as a scaffold for signaling systems. To that effect we compared both behavior and monoaminergic markers in wild type (WT) and PrP(C)-null (PrP(-/-)) mice. PrP(-/-) mice performed poorly when compared with WT in forced swimming, tail suspension, and novelty suppressed feeding tests, typical of depressive-like behavior, but not in the control open field nor rotarod motor tests; cyclic AMP responses to stimulation of D1 receptors by dopamine was selectively impaired in PrP(-/-) mice, and responses to serotonin, but not to norepinephrine, also differed between genotypes. Contents of dopamine, tyrosine hydroxylase, and the 5-HT5A serotonin receptor were increased in the cerebral cortex of PrP(-/-), as compared with WT mice. Microscopic colocalization, as well as binding in overlay assays were found of PrP(C) with both the 5HT5A and D1, but not D4 receptors. The data are consistent with the scaffolding of monoaminergic signaling modules by PrP(C), and may help understand the pathogenesis of clinical depression and neurodegenerative disorders.
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Affiliation(s)
| | | | | | - Jose H Ledo
- Instituto de Bioquímica Médica da UFRJ, Rio de Janeiro 21941-902, Brasil
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Sakudo A, Onodera T. Prion protein (PrP) gene-knockout cell lines: insight into functions of the PrP. Front Cell Dev Biol 2015; 2:75. [PMID: 25642423 PMCID: PMC4295555 DOI: 10.3389/fcell.2014.00075] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Accepted: 12/22/2014] [Indexed: 11/13/2022] Open
Abstract
Elucidation of prion protein (PrP) functions is crucial to fully understand prion diseases. A major approach to studying PrP functions is the use of PrP gene-knockout (Prnp (-/-)) mice. So far, six types of Prnp (-/-) mice have been generated, demonstrating the promiscuous functions of PrP. Recently, other PrP family members, such as Doppel and Shadoo, have been found. However, information obtained from comparative studies of structural and functional analyses of these PrP family proteins do not fully reveal PrP functions. Recently, varieties of Prnp (-/-) cell lines established from Prnp (-/-) mice have contributed to the analysis of PrP functions. In this mini-review, we focus on Prnp (-/-) cell lines and summarize currently available Prnp (-/-) cell lines and their characterizations. In addition, we introduce the recent advances in the methodology of cell line generation with knockout or knockdown of the PrP gene. We also discuss how these cell lines have provided valuable insights into PrP functions and show future perspectives.
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Affiliation(s)
- Akikazu Sakudo
- Laboratory of Biometabolic Chemistry, Faculty of Medicine, School of Health Sciences, University of the Ryukyus Nishihara, Japan
| | - Takashi Onodera
- Research Center for Food Safety, School of Agricultural and Life Sciences, University of Tokyo Tokyo, Japan
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Liebert A, Bicknell B, Adams R. Prion Protein Signaling in the Nervous System—A Review and Perspective. ACTA ACUST UNITED AC 2014. [DOI: 10.4137/sti.s12319] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Prion protein (PrPC) was originally known as the causative agent of transmissible spongiform encephalopathy (TSE) but with recent research, its true function in cells is becoming clearer. It is known to act as a scaffolding protein, binding multiple ligands at the cell membrane and to be involved in signal transduction, passing information from the extracellular matrix (ECM) to the cytoplasm. Its role in the coordination of transmitters at the synapse, glyapse, and gap junction and in short- and long-range neurotrophic signaling gives PrPC a major part in neural transmission and nervous system signaling. It acts to regulate cellular function in multiple targets through its role as a controller of redox status and calcium ion flux. Given the importance of PrPC in cell physiology, this review considers its potential role in disease apart from TSE. The putative functions of PrPC point to involvement in neurodegenerative disease, neuropathic pain, chronic headache, and inflammatory disease including neuroinflammatory disease of the nervous system. Potential targets for the treatment of disease influenced by PrPC are discussed.
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Affiliation(s)
- Ann Liebert
- Faculty of Health Science, University of Sydney, Australia
| | - Brian Bicknell
- Faculty of Health Science, Australian Catholic University, Australia
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