ABCA1/ApoE/HDL Signaling Pathway Facilitates Myelination and Oligodendrogenesis after Stroke

• Published in: International journal of molecular sciences 2020-06, Vol.21 (12), p.4369
• Main Authors: Li, Li, Li, Rongwen, Zacharek, Alex, Wang, Fengjie, Landschoot-Ward, Julie, Chopp, Michael, Chen, Jieli, Cui, Xu
• Format: Article
• Language: English
• Subjects: ABCA1; ABCA1 protein; Animals; ApoE; Apolipoprotein E; Apolipoproteins; Apolipoproteins E - administration & dosage; Apolipoproteins E - pharmacology; ATP Binding Cassette Transporter 1 - genetics; ATP-binding protein; Blood plasma; Cell Movement - drug effects; Cells (biology); Cells, Cultured; Cerebral blood flow; Cerebrospinal fluid; Cerebrospinal Fluid - chemistry; Cholesterol; Disease Models, Animal; Edema; HDL; High density lipoprotein; Humans; Ischemia; Lipoproteins, HDL3 - administration & dosage; Lipoproteins, HDL3 - pharmacology; Male; Maturation; Mice; Myelin; Myelin Sheath - drug effects; Myelin Sheath - metabolism; Myelination; mylination; Occlusion; oligodendrogenesis; Oligodendroglia - cytology; Oligodendroglia - drug effects; Oligodendroglia - metabolism; Organogenesis - drug effects; Primary Cell Culture; Progenitor cells; Recombinant Proteins - administration & dosage; Recombinant Proteins - pharmacology; Signal Transduction; Stroke - drug therapy; Stroke - etiology; Stroke - genetics; Stroke - metabolism; white matter
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21124369

ATP-binding cassette transporter A1 (ABCA1) plays an important role in the regulation of apolipoprotein E (ApoE) and the biogenesis of high-density lipoprotein (HDL) cholesterol in the mammalian brain. Cholesterol is a major source for myelination. Here, we investigate whether ABCA1/ApoE/HDL contribute to myelin repair and oligodendrogenesis in the ischemic brain after stroke. Specific brain ABCA1-deficient (ABCA1 ) and ABCA1-floxed (ABCA1 ) control mice were subjected to permanent distal middle-cerebral-artery occlusion (dMCAo) and were intracerebrally administered (1) artificial mouse cerebrospinal fluid (CSF) as vehicle control, (2) human plasma HDL3, and (3) recombined human ApoE2 starting 24 h after dMCAo for 14 days. All stroke mice were sacrificed 21 days after dMCAo. The ABCA1 -dMCAo mice exhibit significantly reduced myelination and oligodendrogenesis in the ischemic brain as well as decreased functional outcome 21 days after stroke compared with ABCA1 mice; administration of human ApoE2 or HDL3 in the ischemic brain significantly attenuates the deficits in myelination and oligodendrogenesis in ABCA1 -dMCAo mice ( < 0.05, = 9/group). In vitro, ABCA1 reduces ApoE expression and decreases primary oligodendrocyte progenitor cell (OPC) migration and oligodendrocyte maturation; HDL3 and ApoE2 treatment significantly reverses ABCA1 -induced reduction in OPC migration and oligodendrocyte maturation. Our data indicate that the ABCA1/ApoE/HDL signaling pathway contributes to myelination and oligodendrogenesis in the ischemic brain after stroke.