Postmortem brain tissue from people with multiple sclerosis (MS) shows surprising evidence of neurogenesis in the white matter where chronic demyelinated lesions take up residence.
The investigators, led by Bruce D. Trapp, PhD, chairman of the department of neurosciences at the Cleveland Clinic Foundation Lerner Research Institute, provide evidence that neurons destroyed during periods of demyelination may be replaced by new neurons. It appears, according to Dr. Trapp, that the damaged MS brain is trying to repair itself. The study was published July 24 in the online edition of the journal Brain.
Dr. Trapp and his colleagues have been studying interneurons located in the frontal and parietal lobes of the adult human brain. These “white matter neurons” normally help regulate blood flow, but the Ohio researchers became interested in studying the diseased brain to see whether MS pathology includes these interneurons.
STUDY PROTOCOLS, DATA
To discover the fate of white matter interneurons in MS, investigators collected subcortical white matter tissue samples from autopsies in four “normal” control brains, seven newly-formed [one- to two-weeks] MS lesions, and 59 chronic MS lesion samples — of years to decades — from nine patients with MS.
They used immunohistochemistry to stain for the interneurons in the white matter free of lesions and those samples with lesions. All seven tissue samples with acute lesions showed marked loss of interneurons, as did 44 of the 59 chronic lesions.
In the other 15 samples, they found a significant increase (72 percent) in the density of the mature interneurons, an increase in synapses and cells that looked characteristically like immature neurons — evidence, they concluded, of neurogenesis.
Chronic lesions with increased neuronal density also contained a morphologically distinct population of activated microglia, evidence that the brain may have been trying to replace the cells that were destroyed in the lesion.
The presence of a morphologically distinct population does not prove neurogenesis, Dr. Trapp explained, adding that the pr4esence of this “unique” cell population was found only in areas of chronic MS lesions with increased neuronal density. “We speculate that they either play a role in neurogenesis or represent a unique response to the new neurons.”
“The brain never gives up on trying to repair itself,” said Dr. Trapp. “We can literally pick out the lesions with increased neuronal density by the shape of the microglia. The microglial cells here have a distinct shape we have never seen before.” (Microglia are resident immune cells in the brain.)
WHAT THE DATA MEAN: EXPERTS COMMENT
This is the first account of neurogenesis in the human adult MS brain. “It is interesting,” said Steven Goldman, MD, PhD, a professor of neurology and neurosurgery at the University of Rochester in New York. “They have found in the demyelinating tissue that there may be activation of new neurons from endogenous stem or progenitor cells. The science is provocative and solid.”
That the scientists have only a one-time snapshot of the diseased adult brain makes it impossible to know anything about the function of these new neurons. “We just don't know from the work yet whether it is a pathological response or an adaptive response. Either way, it is intriguing,” said Dr. Goldman, who showed in his own laboratory that adult glial progenitor cells can make neurons. The study was published in 2003 in Nature Medicine.
Could activated microglia induce neurogenesis? Investigators are now trying to figure it out in the test tube by putting activated microglia with progenitor stem cells to see whether the mixture can induce the formation of neurons.
In MS, demyelination also extends into the grey matter, where virtually all cerebral neurons live and work. While there is no evidence of inflammation in these lesions in grey matter, there is inflammation in the white matter lesions. This inflammation triggers the death of cells in the white matter.
Scientists have not previously discovered this neurogenesis because most of the work is done in laboratory animals, and only primates and cats have enough white matter neurons to study, said Dr. Trapp. What's more, it has always been hard to study neuronal injury in grey matter because so many neurons populate these regions. White matter, with a small population of neurons, provides a clearer picture of life under the shadow of a demyelinating disease.
It is not clear at all why the chronic lesions have such increased neuronal densities, Dr. Trapp added. Lesions with increased neuronal densities were only present in three of the nine MS brains used in the study. There was no evidence of cell division but these increased densities imply that it is occurring. And of course they don't understand why most of the MS lesions failed to generate new neurons.
Dr. Trapp said that this may be evidence of some kind of self-repair mechanism to replace destroyed neurons. Another possibility is that the cells migrated from other brain regions. But Dr. Trapp said that the cells have such huge dendrites that migration in itself “would be rather amazing.” He is convinced that it is neurogenesis, but he said he has no idea why some brain samples show evidence of this and most do not.
“In the stained tissue sections, some of the lesions with increased neuronal density could be seen with the naked eye,” he said.
Investigators conducted all of the necessary tests to prove that they were indeed neurons — they received ultrastructurally-confirmed synapses, expressed molecules that help regulate blood flow and stained for MAP2, a marker for mature neurons. By contrast, the newly-formed immature cells did not stain for MAP2 because the marker only picks out adult neurons. But these immature cells expressed other neuronal markers.
It is not clear what this will eventually mean for patients with multiple sclerosis. The finding could also lead other investigators to search for signs of neurogenesis in other brain diseases. Dr. Trapp and his colleagues are now looking for molecules that could regulate neurogenesis in the MS brain.
Chang A, Smith MC, Trapp BD, et al. Neurogenesis in the chronic lesions of multiple sclerosis. Brain 2008; E-pub 2008 July 24.
Nunes MC, Roy NS, Goldman SA, et al. Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain. Nature Med 2003;9:439–447.