Ezzat Hashemi PhD, Isha N. Srivastava MD, PhD, Alejandro Aguirre MD, Ezra T. Yoseph BS, Esha Kaushal PhD, Avni Awani PhD, Jae K. Ryu PhD, Katerina Akassoglou PhD, Shahrzad Talebian MSc, Pauline Chu BS, HT (ASCP), Laura Pisani PhD, Patricia Musolino MD, PhD, Lawrence Steinman MD, Kristian Doyle PhD, William H. Robinson MD, PhD, Orr Sharpe MSc, Romain Cayrol MD, PhD, Paul J. Orchard MD, Troy Lund MD, PhD, Hannes Vogel MD, Max Lenail BS, May H. Han MD, Joshua L. Bonkowsky MD, PhD, Keith P. Van Haren MD
{"title":"X-遗传性肾上腺白质营养不良症脑部炎症性脱髓鞘的新型小鼠模型：对发病机制和潜在治疗靶点的洞察。","authors":"Ezzat Hashemi PhD, Isha N. Srivastava MD, PhD, Alejandro Aguirre MD, Ezra T. Yoseph BS, Esha Kaushal PhD, Avni Awani PhD, Jae K. Ryu PhD, Katerina Akassoglou PhD, Shahrzad Talebian MSc, Pauline Chu BS, HT (ASCP), Laura Pisani PhD, Patricia Musolino MD, PhD, Lawrence Steinman MD, Kristian Doyle PhD, William H. Robinson MD, PhD, Orr Sharpe MSc, Romain Cayrol MD, PhD, Paul J. Orchard MD, Troy Lund MD, PhD, Hannes Vogel MD, Max Lenail BS, May H. Han MD, Joshua L. Bonkowsky MD, PhD, Keith P. Van Haren MD","doi":"10.1002/ana.27117","DOIUrl":null,"url":null,"abstract":"<div>\n \n <section>\n \n <h3> Objective</h3>\n \n <p>X-linked adrenoleukodystrophy (ALD) is caused by mutations in <i>ABCD1</i>, a peroxisomal gene. More than half of males with an <i>ABCD1</i> mutation develop inflammatory cerebral demyelination (cALD), but underlying mechanisms remain unknown and therapies are limited. We sought to develop and characterize a mouse model of cALD to facilitate study of disease mechanisms and therapy development.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>We used immunoassays and immunohistochemistry to assess novel (interleukin 18 [IL-18]) and established molecular markers in cerebrospinal fluid (CSF) and postmortem brain tissue from cALD patients. We generated a cALD phenotype in <i>Abcd1-</i>knockout mice using a 2-hit method that combines cuprizone and experimental autoimmune encephalomyelitis models. We then used magnetic resonance imaging (MRI) and immunohistochemistry to assess the fidelity of cALD molecular markers in the mice.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Human and mouse cALD lesions shared histologic features of myelin phagocytosis, myelin loss, abundant microglial activation, T and B-cell infiltration, and astrogliosis. Compared to wild-type controls, <i>Abcd1</i>-knockout mice displayed more cerebral demyelination, blood–brain barrier disruption, and perivascular immune cell infiltration. This enhanced inflammatory response was associated with higher levels of fibrin deposition, oxidative stress, demyelination, and axonal injury. IL-18 immunoreactivity co-localized with perivascular monocytes/macrophages in both human and mouse brain tissue. In cALD patients, CSF IL-18 levels correlated with MRI lesion severity.</p>\n </section>\n \n <section>\n \n <h3> Interpretation</h3>\n \n <p>Our results suggest loss of <i>Abcd1</i> function in mice predisposes to more severe blood–brain barrier disruption, cerebral inflammation driven by the infiltration of peripheral immune cells, demyelination, and axonal damage, replicating human cALD features. This novel mouse model could shed light on cALD mechanisms and accelerate cALD therapy development. ANN NEUROL 2025;97:296–312</p>\n </section>\n </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"97 2","pages":"296-312"},"PeriodicalIF":8.1000,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A Novel Mouse Model for Cerebral Inflammatory Demyelination in X-Linked Adrenoleukodystrophy: Insights into Pathogenesis and Potential Therapeutic Targets\",\"authors\":\"Ezzat Hashemi PhD, Isha N. Srivastava MD, PhD, Alejandro Aguirre MD, Ezra T. Yoseph BS, Esha Kaushal PhD, Avni Awani PhD, Jae K. Ryu PhD, Katerina Akassoglou PhD, Shahrzad Talebian MSc, Pauline Chu BS, HT (ASCP), Laura Pisani PhD, Patricia Musolino MD, PhD, Lawrence Steinman MD, Kristian Doyle PhD, William H. Robinson MD, PhD, Orr Sharpe MSc, Romain Cayrol MD, PhD, Paul J. Orchard MD, Troy Lund MD, PhD, Hannes Vogel MD, Max Lenail BS, May H. Han MD, Joshua L. Bonkowsky MD, PhD, Keith P. Van Haren MD\",\"doi\":\"10.1002/ana.27117\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n <section>\\n \\n <h3> Objective</h3>\\n \\n <p>X-linked adrenoleukodystrophy (ALD) is caused by mutations in <i>ABCD1</i>, a peroxisomal gene. More than half of males with an <i>ABCD1</i> mutation develop inflammatory cerebral demyelination (cALD), but underlying mechanisms remain unknown and therapies are limited. We sought to develop and characterize a mouse model of cALD to facilitate study of disease mechanisms and therapy development.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>We used immunoassays and immunohistochemistry to assess novel (interleukin 18 [IL-18]) and established molecular markers in cerebrospinal fluid (CSF) and postmortem brain tissue from cALD patients. We generated a cALD phenotype in <i>Abcd1-</i>knockout mice using a 2-hit method that combines cuprizone and experimental autoimmune encephalomyelitis models. We then used magnetic resonance imaging (MRI) and immunohistochemistry to assess the fidelity of cALD molecular markers in the mice.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>Human and mouse cALD lesions shared histologic features of myelin phagocytosis, myelin loss, abundant microglial activation, T and B-cell infiltration, and astrogliosis. Compared to wild-type controls, <i>Abcd1</i>-knockout mice displayed more cerebral demyelination, blood–brain barrier disruption, and perivascular immune cell infiltration. This enhanced inflammatory response was associated with higher levels of fibrin deposition, oxidative stress, demyelination, and axonal injury. IL-18 immunoreactivity co-localized with perivascular monocytes/macrophages in both human and mouse brain tissue. In cALD patients, CSF IL-18 levels correlated with MRI lesion severity.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Interpretation</h3>\\n \\n <p>Our results suggest loss of <i>Abcd1</i> function in mice predisposes to more severe blood–brain barrier disruption, cerebral inflammation driven by the infiltration of peripheral immune cells, demyelination, and axonal damage, replicating human cALD features. This novel mouse model could shed light on cALD mechanisms and accelerate cALD therapy development. 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A Novel Mouse Model for Cerebral Inflammatory Demyelination in X-Linked Adrenoleukodystrophy: Insights into Pathogenesis and Potential Therapeutic Targets
Objective
X-linked adrenoleukodystrophy (ALD) is caused by mutations in ABCD1, a peroxisomal gene. More than half of males with an ABCD1 mutation develop inflammatory cerebral demyelination (cALD), but underlying mechanisms remain unknown and therapies are limited. We sought to develop and characterize a mouse model of cALD to facilitate study of disease mechanisms and therapy development.
Methods
We used immunoassays and immunohistochemistry to assess novel (interleukin 18 [IL-18]) and established molecular markers in cerebrospinal fluid (CSF) and postmortem brain tissue from cALD patients. We generated a cALD phenotype in Abcd1-knockout mice using a 2-hit method that combines cuprizone and experimental autoimmune encephalomyelitis models. We then used magnetic resonance imaging (MRI) and immunohistochemistry to assess the fidelity of cALD molecular markers in the mice.
Results
Human and mouse cALD lesions shared histologic features of myelin phagocytosis, myelin loss, abundant microglial activation, T and B-cell infiltration, and astrogliosis. Compared to wild-type controls, Abcd1-knockout mice displayed more cerebral demyelination, blood–brain barrier disruption, and perivascular immune cell infiltration. This enhanced inflammatory response was associated with higher levels of fibrin deposition, oxidative stress, demyelination, and axonal injury. IL-18 immunoreactivity co-localized with perivascular monocytes/macrophages in both human and mouse brain tissue. In cALD patients, CSF IL-18 levels correlated with MRI lesion severity.
Interpretation
Our results suggest loss of Abcd1 function in mice predisposes to more severe blood–brain barrier disruption, cerebral inflammation driven by the infiltration of peripheral immune cells, demyelination, and axonal damage, replicating human cALD features. This novel mouse model could shed light on cALD mechanisms and accelerate cALD therapy development. ANN NEUROL 2025;97:296–312
期刊介绍：
Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.
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