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Chronic white matter atrophy after acute cuprizone exposure may be due to transmissible misfolded proteins
Author(s): ,
A.V. Caprariello
Affiliations:
Clinical Neurosciences, University of Calgary, Calgary, AB, Canada
,
M.L. Morgan
Affiliations:
Clinical Neurosciences, University of Calgary, Calgary, AB, Canada
P.K. Stys
Affiliations:
Clinical Neurosciences, University of Calgary, Calgary, AB, Canada
ECTRIMS Online Library. Caprariello A. Oct 12, 2018; 228903
Andrew V. Caprariello
Andrew V. Caprariello
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Abstract: P1062

Type: Poster Sessions

Abstract Category: Pathology and pathogenesis of MS - Experimental models

Objective: Animal models of progressive MS lag behind those of acute neuroinflammation. A common model of acute demyelination—oral administration of copper-depleting cuprizone (CPZ)—holds promise for defining mechanisms of progressive degeneration. Despite robust repair of acute demyelination, atrophy of white matter occurs months after CPZ cessation (Manrique-Hoyos et al, 2012). Given that copper is a structural determinant of cellular prion protein (PrPc), notable for causing transmissible spongiform encephalopathies in its misfolded form, we hypothesized that acute copper depletion would drive PrPc into pathological conformations that underlie progressive degeneration.
Methodology: CPZ (0.2%) was fed for 6-weeks to mice of various genetic backgrounds: C57Bl/6 wild-type (WT), PrP-null (PrP KO) or PrP-overexpressors (Tga20). CPZ was then withdrawn and pathology was tracked longitudinally over the next 4-7 months by qT2 MRI. Brains were then either fixed for histopathology or frozen and homogenized (10% w/v) for intracerebral inoculation into naïve recipient mice.
Results: As expected, PrP KOs were more prone to acute demyelination than WT mice, whereas Tga20 over-expressors were significantly protected. Despite protection from acute demyelination, months after CPZ cessation, progressive white matter pathology was greater in Tga20 than WT mice. Significant atrophy of the corpus callosum in Tga20 was accompanied by abnormal T2 MRI, axon dropout, and tissue vacuolization. By contrast, PrP KO mice were indistinguishable from untreated, age-matched controls, suggesting a role for PrP in the delayed degeneration resulting from prior CPZ exposure. Transmissible pathology—a trademark of prion disease—was demonstrated by intracerebral injection across two generations of naive recipients, in which severe white matter abnormalities on MRI was observed with inoculation only of CPZ-exposed donor brain homogenates. Accelerated pathology in Tga20 recipients indicated that pathology was directly proportional to PrP substrate.
Conclusions: These results expand the utility of the CPZ model beyond mechanisms of acute demyelination and suggest the importance of copper-dependent PrP structural stability on long-term white matter health. Additionally, these data provide important corroboration of our parallel findings that human MS tissue itself transmits PrP-dependent pathology and also provide a preclinical framework in which to test future therapies for progressive MS.
Disclosure: Andrew V. Caprariello: nothing to disclose
Megan L. Morgan: nothing to disclose
Peter K. Stys: nothing to disclose

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