Is microglial apoptosis an early pathogenic change in cerebral X-linked adrenoleukodystrophy?
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.


CONCLUSIONS
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.
Eichler
Florian S
FS
Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. feichler@partners.org
Ren
Jia-Qian
JQ
Cossoy
Michael
M
Rietsch
Anna M
AM
Nagpal
Sameer
S
Moser
Ann B
AB
Frosch
Matthew P
MP
Ransohoff
Richard M
RM
D000293:Adolescent; D000326:Adrenoleukodystrophy / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D000328:Adult; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers; D002634:Chemotaxis, Leukocyte / Q000235:genetics; D002648:Child; D018450:Disease Progression; D004660:Encephalitis / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D005911:Gliosis / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000473:pathology*; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology; D010587:Phagocytosis / Q000502:physiology; D013997:Time Factors
D015415:Biomarkers; D018836:Inflammation Mediators; D008244:Lysophosphatidylcholines