J. Newcombe et al., LOW-DENSITY-LIPOPROTEIN UPTAKE BY MACROPHAGES IN MULTIPLE-SCLEROSIS PLAQUES - IMPLICATIONS FOR PATHOGENESIS, Neuropathology and applied neurobiology, 20(2), 1994, pp. 152-162
Low density lipoprotein (LDL), the major carrier of plasma cholesterol
, may enter the parenchyma of early multiple sclerosis (MS) lesions as
a result of blood-brain barrier damage. We have used antibodies again
st LDL and epitopes found in LDL oxidized by two peroxidative end-prod
ucts, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), to immunocyt
ochemically stain MS plaques at different stages of pathology. Native
LDL, epitopes of MDA-LDL, peptides of myelin basic protein and neutral
lipid oil red O (ORO) staining were found to be co-localized within f
oamy macrophages in early and actively demyelinating MS plaques. Thus
cholesterol esters, which are seen as Maltese crosses under polarized
light in a proportion of foamy macrophages, appear to be derived from
both LDL and myelin. ORO-negative astrocytes were strongly stained wit
h the antibodies against 4-HNE-LDL and MDA-LDL, suggesting uptake of o
xidatively modified protein products alone. Our findings suggest that
a large proportion of the plasma LDL which enters the parenchyma of MS
plaques is oxidatively modified in the lesion. Lipid peroxidation and
oxidized LDL uptake by activated microglia and infiltrating macrophag
es in the early stages of MS plaque development may play important rol
es in demyelination.