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Is microglial apoptosis an early pathogenic change in cerebral X‐linked adrenoleukodystrophy?
Author(s) -
Eichler Florian S.,
Ren JiaQian,
Cossoy Michael,
Rietsch Anna M.,
Nagpal Sameer,
Moser Ann B.,
Frosch Matthew P.,
Ransohoff Richard M.
Publication year - 2008
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21391
Subject(s) - adrenoleukodystrophy , microglia , lysophosphatidylcholine , white matter , apoptosis , lesion , inflammation , pathology , grey matter , neuroscience , cerebral cortex , biology , medicine , phospholipid , immunology , receptor , biochemistry , magnetic resonance imaging , peroxisome , radiology , membrane , phosphatidylcholine
Abstract Objective Mutations in the X‐linked adrenoleukodystrophy (X‐ALD) protein cause accumulation of unbranched saturated very‐long‐chain fatty acids, particularly in brain and adrenal cortex. In humans, the genetic defect causes progressive inflammatory demyelination in the brain, where very‐long‐chain fatty acids accumulate within phospholipid fractions such as lysophosphatidylcholine. Methods To address mechanisms of inflammation, we studied microglial activation in human ALD (10 autopsies) and lysophosphatidylcholine (C24:0) injection into the parietal cortex of mice. Results Unexpectedly, we found a zone lacking microglia within perilesional white matter, immediately beyond the actively demyelinating lesion edge. Surrounding this zone we observed clusters of activated and apoptotic microglia within subcortical white matter. Lysophosphatidylcholine (C24:0) injection in mice led to widespread microglial activation and apoptosis. Interpretation Our data suggest that the distinct mononuclear phagocytic cell response seen in cerebral X‐ALD results, at least in part, from aberrant signaling to cognate receptors on microglia. Our findings support a hypothesis that microglial apoptosis in perilesional white matter represents an early stage in lesion evolution and may be an appropriate target for intervention in X‐ALD patients with evidence of cerebral demyelination. Ann Neurol 2008