Abstract Details

Title A Novel Mouse Model of Cerebral Demyelination in X-linked Adrenoleukodystrophy Highlights NLRP3 Activation in Lesion Pathogenesis

Topic General Neurology

Presentation(s) P11 - Poster Session 11 (5:30 PM-6:30 PM)

Poster/Presentation
Number 4-004

Objective

We sought to create and characterize a mouse model of cALD that facilitate the study of disease pathogenesis and therapy development. We also sought to cross-validate two potential therapeutic targets, fibrinogen and NLRP3 inflammasome activation pathways in cALD postmortem humans’ brain tissues and cALD mouse model.

Background X-linked adrenoleukodystrophy (ALD) is caused by mutations in the ABCD1 encoding a peroxisomal transporter. Most males with ALD develop inflammatory cerebral demyelination (cALD), but the underlying mechanisms are unknown due to the lack of cALD phenotype in the Abcd1-null mouse.

Design/Methods

We generated a cALD phenotype in 8 week-old, male Abcd1-null mice by deploying a two-hit method combining cuprizone and experimental autoimmune encephalomyelitis (EAE) models. We employed in vivo MRI and immunohistochemistry to evaluate myelin loss, gliosis, blood-brain barrier disruption, immune cell infiltration, fibrin deposition, oxidative stress, and Nlrp3 inflammasome activation in mice. We used immunohistochemistry and bead-based immunoassay to evaluate IL-18, NLRP3 inflammasome activation, in CSF and post-mortem human cALD brain tissue.

Results : MRI studies revealed T2 hyperintensities and post-gadolinium enhancement in the medial corpus callosum of cALD mice, similar to human cALD lesions. Both human and mouse cALD lesions shared common histologic features of myelin phagocytosis, myelin loss, abundant microglial activation, T and B-cell infiltration, and astrocytosis. Compared to wild-type controls, Abcd1-null mice had more severe cerebral inflammation, demyelination, fibrin deposition, oxidative stress, and IL-18 activation. IL-18 immunoreactivity co-localized with macrophages/microglia in the perivascular region of both human and mouse brain tissue.

Conclusions This novel mouse model of cALD suggests loss of Abcd1 function predisposes to more severe cerebral inflammation, oxidative stress, fibrin deposition, and Nlrp3 pathway activation, which parallels the findings seen in patients with cALD. We expect this model to enable long-sought investigations into cALD mechanisms and accelerate development of candidate therapies for lesion prevention, cessation, and remyelination.

Authors/Disclosures
Ezzat Hashemi (Stanford University) PRESENTER	No disclosure on file
Isha Srivastava, MD, PhD (Neurology Residency Office)	Dr. Srivastava has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Ionis.
Alejandro Aguirre	No disclosure on file
Ezra Yoseph	No disclosure on file
Esha Kaushal, PhD (Stanford)	Dr. Kaushal has nothing to disclose.
Avni Awani	No disclosure on file
Jae Kyu Ryu (Gladstone Institutes)	No disclosure on file
Shahrzad Talebian (stanford)	No disclosure on file
Pauline Chu	No disclosure on file
Lawrence Steinman, MD, FAAN (Stanford Medicine)	Dr. Steinman has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for TG Therapeutics. Dr. Steinman has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for 180 Life Sciences. Dr. Steinman has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for BioAtla. Dr. Steinman has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Pasithea. Dr. Steinman has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Atreca. Dr. Steinman has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Wilmer Hale Cutler Pickering. Dr. Steinman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bristol Meyers Squibb. Dr. Steinman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics. Dr. Steinman has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for National Academy of Sciences. Dr. Steinman has received personal compensation in the range of $100,000-$499,999 for serving as an Expert Witness for Gibson Dunn. The institution of Dr. Steinman has received research support from Roche. The institution of Dr. Steinman has received research support from Novartis. Dr. Steinman has received intellectual property interests from a discovery or technology relating to health care.
Paul Orchard	No disclosure on file
Troy Lund	No disclosure on file
May Han, MD (Stanford University)	Dr. Han has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Han has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arena Pharmaceuticals.
Joshua Bonkowsky, MD, PhD	Dr. Bonkowsky has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Denali. Dr. Bonkowsky has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurogene. Dr. Bonkowsky has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Passage Bio. Dr. Bonkowsky has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Autobahn. Dr. Bonkowsky has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Dr. Bonkowsky has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ionis. Dr. Bonkowsky has stock in Orchard. The institution of Dr. Bonkowsky has received research support from NIH. The institution of Dr. Bonkowsky has received research support from ELA. An immediate family member of Dr. Bonkowsky has received intellectual property interests from a discovery or technology relating to health care. Dr. Bonkowsky has received publishing royalties from a publication relating to health care. Dr. Bonkowsky has received publishing royalties from a publication relating to health care.
Keith Van Haren, MD (Stanford Univ Neurology)	Dr. Van Haren has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Viking Therapeutics. Dr. Van Haren has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bluebirdbio. Dr. Van Haren has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Orpheris. Dr. Van Haren has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Autobahn. Dr. Van Haren has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for PRIME, Inc. The institution of Dr. Van Haren has received research support from Minoryx. The institution of Dr. Van Haren has received research support from bluebirdbio. Dr. Van Haren has a non-compensated relationship as a Board of Directors with ALD Connect that is relevant to AAN interests or activities. Dr. Van Haren has a non-compensated relationship as a Scientific Advisory Board with United Leukodystrophy Foundation that is relevant to AAN interests or activities.

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