Krabbe disease (KD) is an inherited
neurological disorder caused by the deficiency of
galactocerebrosidase activity resulting in accumulation of
psychosine, which leads to energy depletion, loss of oligodendrocytes, induction of
gliosis, and
inflammation by astrocytes in CNS. In this study, for the first time, we report the regulation of 'cellular energy switch,'
AMP-activated protein kinase (AMPK), by
psychosine in oligodendrocytes and astrocytes.
Psychosine treatment significantly down-regulated AMPK activity, resulting in increased biosynthesis of
lipids including
cholesterol and
free fatty acid in oligodendrocytes cell line (MO3.13) and primary astrocytes. Pharmacological activator of AMPK, 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (
AICAR) attenuated the
psychosine-mediated down-regulation of AMPK and restored altered biosynthesis of
lipids.
AICAR treatment also down-regulated
psychosine induced expression of proinflammatory
cytokines and
inducible nitric oxide synthase in primary astrocytes. However,
AICAR treatment had no effect on
psychosine induced-
reactive oxygen species generation,
arachidonic acid release, and death of oligodendrocytes; suggesting the specific role of AMPK in regulation of
psychosine-mediated inflammatory response of astrocytes but not in cell death of oligodendrocytes. This study delineates an explicit role for AMPK in
psychosine induced
inflammation in astrocytes without directly affecting the cell death of oligodendrocytes. It also suggests that AMPK activating agents act as
anti-inflammatory agents and can hold a therapeutic potential in
Krabbe disease/twitcher disease, particularly when used in combination with drugs, which protect oligodendrocyte cell loss, such as
sPLA2 inhibitor [Giri et al., J.
Lipid Res. 47 (2006), 1478].