Temporal Dynamics of CNS Cholesterol Esters Correlate with Demyelination and Remyelination

Elevated cholesterol
ester levels have been observed
in the CNS
of patients with neurological diseases; yet, the source of cholesterol
ester accumulation and whether it is directly linked to demyelination
remain undefined. This study investigates the temporal dynamics of
cholesterol esters using the Plp1-iCKO-Myrf mouse model, which features distinct phases of demyelination and
remyelination. Our findings reveal that cholesterol ester levels increased
with demyelination in both the brain and spinal cord. In the brain,
cholesterol esters declined to normal levels during remyelination,
whereas cholesterol esters remained elevated in the spinal cord, which
had limited remyelination. Expression of acetyl-CoA-acyltransferase
1 (ACAT1) and lecithin-cholesterol acyltransferase (LCAT) were elevated
during demyelination, implying the potential involvement of both proteins
in the formation of cholesterol esters. Colocalization studies revealed
that ACAT1 is predominantly expressed by microglia and LCAT is predominantly
expressed by astrocytes during demyelination, highlighting the active
roles of glial cells in cholesterol ester metabolism. In addition,
we showed that administering the remyelinating drug, Sob-AM2, effectively
reduced the level of cholesterol ester accumulation in the brain during
demyelination, underscoring the potential that manipulating cholesterol
ester regulatory pathways may offer for restoring cholesterol homeostasis
and promoting remyelination in demyelinating diseases.