LINGO-1 antibody ameliorates myelin impairment and spatial memory deficits in experimental autoimmune encephalomyelitis mice.

Jun-Jun Sun,Zhi-Jun Zhang,Lin Xu,Qing-Guo Ren

doi:10.1038/srep14235

Abstract

More than 50% of multiple sclerosis patients develop cognitive impairment. However, the underlying mechanisms are still unclear, and there is no effective treatment. LINGO-1 (LRR and Ig domain containing NOGO receptor interacting protein 1) has been identified as an inhibitor of oligodendrocyte differentiation and myelination. Using the experimental autoimmune encephalomyelitis (EAE) mouse model, we assessed cognitive function at early and late stages of EAE, determined brain expression of myelin basic protein (MBP) and investigated whether the LINGO-1 antibody could restore deficits in learning and memory and ameliorate any loss of MBP. We found that deficits in learning and memory occurred in late EAE and identified decreased expression of MBP in the parahippocampal cortex (PHC) and fimbria-fornix. Moreover, the LINGO-1 antibody significantly improved learning and memory in EAE and partially restored MBP in PHC. Furthermore, the LINGO-1 antibody activated the AKT/mTOR signaling pathway regulating myelin growth. Our results suggest that demyelination in the PHC and fimbria-fornix might contribute to cognitive deficits and the LINGO-1 antibody could ameliorate these deficits by promoting myelin growth in the PHC. Our research demonstrates that LINGO-1 antagonism may be an effective approach to the treatment of the cognitive impairment of multiple sclerosis patients.

Highlights

Inflammation[9,10]
LINGO-1 (Leucine rich repeat and Ig domain containing NOGO receptor interacting protein 1) is an important transmembrane protein that is expressed in oligodendrocytes and neurons in the central nervous system (CNS); it is a key inhibitor of oligodendrocyte precursor cells (OPCs) differentiation and myelination[20]
The results showed that the EAE mice have no anxiety and depression-like behavior in the two periods (Supplementary Figs S1–S3 online)

Summary

Introduction

Inflammation[9,10]. the impairment of myelin is a prominent feature of many neurological diseases and complex neuropsychiatric disorders including MS and Alzheimer’s disease[11,12,13]. Consistent with postmortem clinical research, preclinical studies have demonstrated demyelination in the hippocampus (CA1) in the EAE model[5]. Further research by Mi et al (2007) demonstrates that the LINGO-1 antagonist promotes spinal cord remyelination and functional recovery in EAE mice[23]. These studies provide the evidence to confirm that antagonism of LINGO-1 is one of promising approaches for the treatment of demyelinating diseases. It has been well demonstrated that the LINGO-1 antibody promotes remyelination; whether the LINGO-1 antibody could effectively restore the cognitive impairment in EAE mice is still unknown. The LINGO-1 antibody may be an effective drug for ameliorating the cognitive impairment of demyelinating diseases in the CNS

Methods

Results

Conclusion