TY - JOUR
T1 - ABCA1 influences neuroinflammation and neuronal death
AU - Karasinska, Joanna M.
AU - de Haan, Willeke
AU - Franciosi, Sonia
AU - Ruddle, Piers
AU - Fan, Jianjia
AU - Kruit, Janine K.
AU - Stukas, Sophie
AU - Lütjohann, Dieter
AU - Gutmann, David H.
AU - Wellington, Cheryl L.
AU - Hayden, Michael R.
N1 - Funding Information:
This study was supported by a grant from the Canadian Institutes of Health Research (CIHR MOP-106684 ).
PY - 2013/6
Y1 - 2013/6
N2 - 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.
AB - 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.
KW - ABCA1
KW - Apolipoproteins
KW - Brain cholesterol metabolism
KW - Neurodegeneration
KW - Neuroinflammation
UR - http://www.scopus.com/inward/record.url?scp=84876309874&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2013.01.018
DO - 10.1016/j.nbd.2013.01.018
M3 - Article
C2 - 23376685
AN - SCOPUS:84876309874
SN - 0969-9961
VL - 54
SP - 445
EP - 455
JO - Neurobiology of Disease
JF - Neurobiology of Disease
ER -