Contributions
Abstract: P441
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 13 Experimental models
Background: Primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS) patients all experience neurological decline over time. However, there are differences in their lesion distribution and extent of inflammation. It remains unclear whether the pathophysiological mechanisms contributing to clinical progression in PPMS and SPMS are the same.
Objectives: To establish an experimental model to investigate disease pathogenesis underlying PPMS and SPMS.
Methods: Mice underwent laminectomies at cervical levels 4 and 5 to expose the underlying spinal cord and cerebrospinal fluid (CSF) was injected under the dura mater into the subarachnoid space. Control animals were injected with saline or CSF from healthy donors. Functional deficits were assessed by evaluating forelimb reaching, gripping and tail rigidity at 1 day post injection (DPI), 3 DPI, and 7 DPI. Mice were perfused at these same time points following CSF delivery. Spinal cords were post-fixed overnight in 4% paraformaldehyde, cryoprotected in 30% sucrose, then cryosectioned for histological analyses. RNA was extracted from cervical spinal cords at 1DPI for qPCR analyses.
Results: Mice injected with PPMS CSF displayed significantly higher behavioral deficit scores in comparison to mice injected with SPMS and control CSF. Mice injected with SPMS CSF did not show functional impairments and scores were not statistically different from controls. Spinal cords from mice injected with PPMS CSF exhibited evidence of astrogliosis at all time points examined, as revealed by significantly increased GFAP immunostaining in the dorsal white matter. However, astrogliosis was not observed in mice injected with SPMS CSF. Similarly, a significant increase in immunostaining intensity for SMI-32, a marker of axonal damage, was observed in mice injected with PPMS CSF, but not SPMS CSF. In contrast, Iba1 immunostaining was similar in all groups, suggesting that microglia do not play a major role in contributing to deficits and pathology observed in PPMS CSF-injected mice. Preliminary qPCR data show that PPMS CSF-injected mice have greater changes in GFAP mRNA expression than other groups.
Conclusions: Motor deficits and spinal cord pathology are induced by PPMS CSF, but not SPMS CSF, suggesting that pathophysiological mechanisms underlying PPMS and SPMS may be different and merit further investigation.
Disclosure:
Jamie K. Wong: Nothing to disclose
Nathan J. Kung: Nothing to disclose
Jessie Z. Huang: Nothing to disclose
Saud A. Sadiq: Nothing to disclose
Funding source: Tisch MS Research Center of New York (private funds)
Abstract: P441
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 13 Experimental models
Background: Primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS) patients all experience neurological decline over time. However, there are differences in their lesion distribution and extent of inflammation. It remains unclear whether the pathophysiological mechanisms contributing to clinical progression in PPMS and SPMS are the same.
Objectives: To establish an experimental model to investigate disease pathogenesis underlying PPMS and SPMS.
Methods: Mice underwent laminectomies at cervical levels 4 and 5 to expose the underlying spinal cord and cerebrospinal fluid (CSF) was injected under the dura mater into the subarachnoid space. Control animals were injected with saline or CSF from healthy donors. Functional deficits were assessed by evaluating forelimb reaching, gripping and tail rigidity at 1 day post injection (DPI), 3 DPI, and 7 DPI. Mice were perfused at these same time points following CSF delivery. Spinal cords were post-fixed overnight in 4% paraformaldehyde, cryoprotected in 30% sucrose, then cryosectioned for histological analyses. RNA was extracted from cervical spinal cords at 1DPI for qPCR analyses.
Results: Mice injected with PPMS CSF displayed significantly higher behavioral deficit scores in comparison to mice injected with SPMS and control CSF. Mice injected with SPMS CSF did not show functional impairments and scores were not statistically different from controls. Spinal cords from mice injected with PPMS CSF exhibited evidence of astrogliosis at all time points examined, as revealed by significantly increased GFAP immunostaining in the dorsal white matter. However, astrogliosis was not observed in mice injected with SPMS CSF. Similarly, a significant increase in immunostaining intensity for SMI-32, a marker of axonal damage, was observed in mice injected with PPMS CSF, but not SPMS CSF. In contrast, Iba1 immunostaining was similar in all groups, suggesting that microglia do not play a major role in contributing to deficits and pathology observed in PPMS CSF-injected mice. Preliminary qPCR data show that PPMS CSF-injected mice have greater changes in GFAP mRNA expression than other groups.
Conclusions: Motor deficits and spinal cord pathology are induced by PPMS CSF, but not SPMS CSF, suggesting that pathophysiological mechanisms underlying PPMS and SPMS may be different and merit further investigation.
Disclosure:
Jamie K. Wong: Nothing to disclose
Nathan J. Kung: Nothing to disclose
Jessie Z. Huang: Nothing to disclose
Saud A. Sadiq: Nothing to disclose
Funding source: Tisch MS Research Center of New York (private funds)