A Novel Mouse Model for Cerebral Inflammatory Demyelination in X-Linked Adrenoleukodystrophy: Insights into Pathogenesis and Potential Therapeutic Targets

被引：0

作者：

Hashemi, Ezzat ^{[1
]}

Srivastava, Isha N. ^{[1
]}

Aguirre, Alejandro ^{[1
]}

Yoseph, Ezra T. ^{[1
]}

Kaushal, Esha ^{[1
]}

Awani, Avni ^{[1
]}

Ryu, Jae K. ^{[2
,3
,4
,5
]}

Akassoglou, Katerina ^{[2
,3
,4
,5
]}

Talebian, Shahrzad ^{[1
]}

Chu, Pauline ^{[6
]}

Pisani, Laura ^{[7
]}

Musolino, Patricia ^{[8
,9
]}

Steinman, Lawrence ^{[1
]}

Doyle, Kristian ^{[10
]}

Robinson, William H. ^{[11
]}

Sharpe, Orr ^{[11
]}

Cayrol, Romain ^{[12
]}

Orchard, Paul J. ^{[13
]}

Lund, Troy ^{[13
]}

Vogel, Hannes ^{[14
]}

Lenail, Max ^{[1
]}

Han, May H. ^{[1
]}

Bonkowsky, Joshua L. ^{[15
,16
,17
]}

Van Haren, Keith P. ^{[1
,18
]}

机构：

[1] Stanford Univ, Dept Neurol & Neurol Sci, Sch Med, 750 Welch Rd,Ste 317, Palo Alto, CA 94304 USA

[2] Gladstone Inst Neurol Dis, San Francisco, CA USA

[3] Ctr Neurovasc Brain Immunol Gladstone, San Francisco, CA USA

[4] UCSF, San Francisco, CA USA

[5] Univ Calif San Francisco, Weill Inst Neurosci, Dept Neurol, San Francisco, CA 94143 USA

[6] Stanford Univ, Stanford Human Res Histol Core, Sch Med, Stanford, CA 94305 USA

[7] Stanford Univ, Sch Med, Sch Med Stanford, Stanford, CA 94305 USA

[8] Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA

[9] Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA USA

[10] Univ Arizona, Dept Immunobiol, Tucson, AZ USA

[11] Stanford Univ, Sch Med, Dept Immunol & Rheumatol, Stanford, CA 94305 USA

[12] Univ Montreal, Dept Clin Lab Med, Dept Pathol, Montreal, PQ, Canada

[13] Univ Minnesota, Div Pediat Blood & Marrow Transplantat, Minneapolis, MN USA

[14] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA USA

[15] Univ Utah, Sch Med, Dept Pediat, Sch Med, Salt Lake City, UT USA

[16] Intermt Healthcare, Primary Childrens Hosp, Salt Lake City, UT 84111 USA

[17] Primary Childrens Ctr Personalized Med, Salt Lake City, UT USA

[18] Stanford Univ, Dept Pediat, Sch Med, Stanford, CA 94305 USA

来源：

ANNALS OF NEUROLOGY | 2024年

关键词：

EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; ADRENO-LEUKODYSTROPHY; OXIDATIVE STRESS; ABCD1; CUPRIZONE; CELLS; OLIGODENDROCYTES; INACTIVATION; LESION; GENE;

D O I：

10.1002/ana.27117

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

ObjectiveX-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.MethodsWe 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.ResultsHuman 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.InterpretationOur 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 2024

引用

页数：17

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