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J Neuroinflammation. 2019 Feb 8;16(1):28. doi: 10.1186/s12974-019-1420-9.

Semaphorin4A causes loss of mature oligodendrocytes and demyelination in vivo.

Author information

1
Department of Neurosurgery, Penn State University College of Medicine, 500 University Drive, Hershey, PA, 17033, USA.
2
Department of Genomic Medicine, Cleveland Clinic/Lerner Research Institute, Cleveland, OH, USA.
3
Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA.
4
Department of Neurosurgery, Penn State University College of Medicine, 500 University Drive, Hershey, PA, 17033, USA. jconnor@pennstatehealth.psu.edu.

Abstract

BACKGROUND:

Inappropriate contact between the immune system and the central nervous system is thought to be a cause of demyelination. We previously reported the ability of the class IV semaphorin, Semaphorin4A (Sema4A), to induce apoptosis in human oligodendrocytes; however, these results have yet to be translated to an in vivo setting. Importantly, HIV-associated neurocognitive disorder remains a significant complication for patients on combined anti-retroviral therapy, with white matter damage seen on MRI.

METHODS:

Human cerebrospinal fluid and serum was assayed for Sema4A using a Sema4A-specific ELISA. Wild-type mice were injected with Sema4A via stereotaxic infusion. Data was assessed for significance using unpaired t tests, comparing the corpus callosum of PBS-injected mice versus Sema4A-injected mice.

RESULTS:

Here, we demonstrate elevated levels of Sema4A in the cerebrospinal fluid and serum of people with HIV infection. Furthermore, we demonstrate that direct injection of Sema4A into the corpus callosum of mice results in loss of myelin architecture and decreased myelin, concomitant with apoptosis of mature myelinating oligodendrocytes. Sema4A injection also causes increased activation of microglia.

CONCLUSIONS:

Taken together, our data further establish Sema4A as a potentially significant mediator of demyelinating diseases and a direct connection between the immune system and oligodendrocytes.

KEYWORDS:

Apoptosis; Demyelination; HIV; Oligodendrocyte; Sema4A; White matter

PMID:
30736794
PMCID:
PMC6368782
DOI:
10.1186/s12974-019-1420-9
[Indexed for MEDLINE]
Free PMC Article

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