ATP-binding cassette transporter A1 (ABCA1) mediates cellular
cholesterol efflux in the brain and influences whole brain
cholesterol homeostasis. Activation of
liver X receptors (LXRs),
transcription factors that increase the expression of
cholesterol transport genes including ABCA1, reduces
neuroinflammation and pathology in neurodegenerative animal models suggesting that in addition to its involvement in
cholesterol transport, ABCA1 may play a role in modulating the inflammatory response in the brain. We investigated the cell-type specific role of ABCA1 in
neuroinflammation in vivo using mice specifically lacking brain ABCA1 (ABCA1(-B/-B)) as well as mice lacking neuronal (ABCA1(-N/-N)) and astrocytic (ABCA1(-Ast/-Ast)) ABCA1. ABCA1(-B/-B) mice exhibit cortical
astrogliosis, increased inflammatory gene expression as well as activation of
mitogen-activated protein kinases (MAPKs) following acute
lipopolysaccharide (LPS) administration. Microglia cultured from ABCA1(-B/-B) mice exhibit augmented LPS-induced secretion of
tumor necrosis factor α (TNFα) and decreased phagocytic activity, indicating an increase in a pro-inflammatory response. ABCA1(-N/-N) mice develop
astrogliosis but show no change in inflammatory gene expression. Intriguingly, ABCA1(-Ast/-Ast) mice show neither
astrogliosis nor elevated expression of inflammatory markers. Cortical
apolipoprotein E (
apoE) levels are reduced in ABCA1(-Ast/-Ast) but not in ABCA1(-N/-N) mice, providing in vivo evidence for the specific role of astrocyte ABCA1 in regulating brain
apoE levels. Interestingly, cortical neuronal death is increased in 17month-old ABCA1(-B/-B) mice but not in ABCA1(-N/-N) or ABCA1(-Ast/-Ast) mice. Our findings suggest that coordinated ABCA1 activity across neurons and glial cells influences
neuroinflammation and neurodegeneration.