Objective
Generation and differentiation of new oligodendrocytes in demyelinated white matter is the best described repair process in the adult human brain. However, remyelinating capacity falters with age in patients with multiple sclerosis. (MS). Since demyelination of cerebral cortex is extensive in brains from MS patients, we investigated the capacity of cortical lesions to remyelinate and directly compared the extent of remyelination in lesions that involve cerebral cortex and adjacent subcortical white matter.
Methods
Postmortem brain tissue from 22 patients with MS (age 27 to 77 years) and 6 subjects without brain disease were analyzed. Regions of cerebral cortex with reduced myelin were examined for remyelination, oligodendrocyte progenitor cells, reactive astrocytes, and molecules that inhibit remyelination.
Results
“New” oligodendrocytes that were actively forming myelin sheaths were identified in 30/42 remyelinated subpial cortical lesions, including lesions from three patients in their 70's. Oligodendrocyte progenitor cells were not decreased in demyelinated or remyelinated cortices when compared to adjacent normal-appearing cortex or controls. In demyelinated lesions involving cortex and adjacent white matter, the cortex showed greater remyelination, more actively remyelinating oligodendrocytes and fewer reactive astrocytes. Astrocytes in the white-matter, but not in cortical portions of these lesions, significantly up-regulate CD44, hyaluronan, and versican, molecules that form complexes that inhibit oligodendrocyte maturation and remyelination.
Interpretation
Endogenous remyelination of the cerebral cortex occurs in individuals with MS regardless of disease duration or chronological age of the patient. Cortical remyelination should be considered as a primary outcome measure in future clinical trials testing remyelination therapies.
Background
Hippocampal demyelination, a common feature of postmortem multiple
sclerosis (MS) brains, reduces neuronal gene expression and is a likely
contributor to the memory impairment that is found in greater than 40% of
individuals with (MS). How demyelination alters neuronal gene expression is
unknown.
Methods
To explore if loss of hippocampal myelin alters expression of
neuronal microRNAs (miRNA), we compared miRNA profiles from myelinated and
demyelinated hippocampi from postmortem MS brains and performed validation
studies.
Findings
A network-based interaction analysis depicts a correlation between
increased neuronal miRNAs and decreased neuronal genes identified in our
previous study. The neuronal miRNA miR-124, was increased in demyelinated MS
hippocampi and targets mRNAs encoding 26 neuronal proteins that were
decreased in demyelinated hippocampus, including the ionotrophic glutamate
receptors, AMPA 2 and AMPA3. Hippocampal demyelination in mice also
increased miR-124, reduced expression of AMPA receptors and decreased memory
performance in water maze tests. Remyelination of the mouse hippocampus
reversed these changes.
Conclusion
We establish here that myelin alters neuronal gene expression and
function by modulating the levels of the neuronal miRNA miR-124. Inhibition
of miR-124 in hippocampal neurons may provide a therapeutic approach to
improve memory performance in MS patients.
Multiple Sclerosis (MS) is an immune-mediated demyelinating disease of the human central nervous system (CNS). Memory impairments and hippocampal demyelination are common features in MS patients. Our previous data have shown that demyelination alters neuronal gene expression in the hippocampus. DNA methylation is a common epigenetic modifier of gene expression. In this study, we investigated whether DNA methylation is altered in MS hippocampus following demyelination. Our results show that mRNA levels of DNA methyltransferase were increased in demyelinated MS hippocampus, while de-methylation enzymes were decreased. Comparative methylation profiling identify hypo-methylation within upstream sequences of 6 genes and hyper-methylation of 10 genes in demyelinated MS hippocampus. Genes identified in the current study were also validated in an independent microarray dataset generated from MS hippocampus. Independent validation using RT-PCR revealed that DNA methylation inversely correlated with mRNA levels of the candidate genes. Queries across cell-specific databases revealed that a majority of the candidate genes are expressed by astrocytes and neurons in mouse and human CNS. Taken together, our results expands the list of genes previously identified in MS hippocampus and establish DNA methylation as a mechanism of altered gene expression in MS hippocampus.
Laser-induced retinal injuries resulted in circulating anti-retinal antibodies that were detectable 3 months after the injury. The response appeared to vary with the severity of the laser retinal damage. The identification of the candidate antigens in this study suggest that this approach may permit future development of new diagnostic methods for retinal injuries.
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