TY - JOUR
T1 - Liver X receptor activation enhances cholesterol loss from the brain, decreases neuroinflammation, and increases survival of the NPC1 mouse
AU - Repa, Joyce J.
AU - Li, Hao
AU - Frank-Cannon, Tamy C.
AU - Valasek, Mark A.
AU - Turley, Stephen D.
AU - Tansey, Malú G.
AU - Dietschy, John M.
PY - 2007/12/26
Y1 - 2007/12/26
N2 - Although cholesterol is a major component of the CNS, there is little information on how or whether a change in sterol flux across the blood- brain barrier might alter neurodegeneration. In Niemann-Pick type C (NPC) disease, a mutation in NPC1 protein causes unesterified cholesterol to accumulate in the lysosomal compartment of every cell, including neurons and glia. Using the murine model of this disease, we used genetic and pharmacologic approaches in an attempt to alter cholesterol homeostasis across the CNS. Genetic deletion of the sterol transporters ATP-binding cassette transporter A1 (ABCA1) and low-density lipoprotein receptor in the NPC1 mouse did not affect sterol balance or longevity. However, deletion of the nuclear receptor, liver X receptor β (LXRβ), had an adverse effect on progression of the disease. We therefore tested the effects of increasing LXR activity by oral administration of a synthetic ligand for this transcription factor. Treatment with this LXR agonist increased cholesterol excretion out of brain from 17 to 49 μg per day, slowed neurodegeneration, and prolonged life. This agonist did not alter synthesis of cholesterol or expression of genes associated with the formation of 24(S)-hydroxycholesterol or neurosteroids such as CYP46A1, 3αHSD, and CYP11A1. However, levels of the sterol transporters ABCA1 and ATP-binding cassette transporter G1 were increased. Concomitantly, markers of neuroinflammation, CD14, MAC1, CD11c, and inducible nitric oxide synthase, were reduced, and microglia reverted from their amoeboid, active form to a ramified, resting configuration. Thus, LXR activation resulted in increased cholesterol excretion from the brain, decreased neuroinflammation, and deactivation of microglia to slow neurodegeneration and extend the lifespan of the NPC1 mouse.
AB - Although cholesterol is a major component of the CNS, there is little information on how or whether a change in sterol flux across the blood- brain barrier might alter neurodegeneration. In Niemann-Pick type C (NPC) disease, a mutation in NPC1 protein causes unesterified cholesterol to accumulate in the lysosomal compartment of every cell, including neurons and glia. Using the murine model of this disease, we used genetic and pharmacologic approaches in an attempt to alter cholesterol homeostasis across the CNS. Genetic deletion of the sterol transporters ATP-binding cassette transporter A1 (ABCA1) and low-density lipoprotein receptor in the NPC1 mouse did not affect sterol balance or longevity. However, deletion of the nuclear receptor, liver X receptor β (LXRβ), had an adverse effect on progression of the disease. We therefore tested the effects of increasing LXR activity by oral administration of a synthetic ligand for this transcription factor. Treatment with this LXR agonist increased cholesterol excretion out of brain from 17 to 49 μg per day, slowed neurodegeneration, and prolonged life. This agonist did not alter synthesis of cholesterol or expression of genes associated with the formation of 24(S)-hydroxycholesterol or neurosteroids such as CYP46A1, 3αHSD, and CYP11A1. However, levels of the sterol transporters ABCA1 and ATP-binding cassette transporter G1 were increased. Concomitantly, markers of neuroinflammation, CD14, MAC1, CD11c, and inducible nitric oxide synthase, were reduced, and microglia reverted from their amoeboid, active form to a ramified, resting configuration. Thus, LXR activation resulted in increased cholesterol excretion from the brain, decreased neuroinflammation, and deactivation of microglia to slow neurodegeneration and extend the lifespan of the NPC1 mouse.
KW - 24(S)-hydroxycholesterol
KW - Astroglia
KW - Blood- brain barrier
KW - Microglia
KW - Nuclear receptors
KW - Purkinje cells
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U2 - 10.1523/JNEUROSCI.4823-07.2007
DO - 10.1523/JNEUROSCI.4823-07.2007
M3 - Article
C2 - 18160655
AN - SCOPUS:37549037886
SN - 0270-6474
VL - 27
SP - 14470
EP - 14480
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 52
ER -