Abstract
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-B/-B) and ABCA1-floxed (ABCA1fl/fl) 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-B/-B–dMCAo mice exhibit significantly reduced myelination and oligodendrogenesis in the ischemic brain as well as decreased functional outcome 21 days after stroke compared with ABCA1fl/fl mice; administration of human ApoE2 or HDL3 in the ischemic brain significantly attenuates the deficits in myelination and oligodendrogenesis in ABCA1-B/-B–dMCAo mice ( p < 0.05, n = 9/group). In vitro, ABCA1-B/-B reduces ApoE expression and decreases primary oligodendrocyte progenitor cell (OPC) migration and oligodendrocyte maturation; HDL3 and ApoE2 treatment significantly reverses ABCA1-B/-B-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.
Highlights
Stroke is a major cause of white matter (WM) damage, which induces long-term disability due to the limited axonal regeneration and remyelination in the inhibitory environment of the adult mammalian central nervous system (CNS) [1–3]
Our previous study showed that ATP-binding cassette transporter A1 (ABCA1)-deficient (ABCA1-B/-B) mice exhibited a marginal increase (p = 0.052) in lesion volume compared with ABCA1-floxed (ABCA1fl/fl) mice measured 7 days after stroke, with the lesion in ABCA1-B/-B stroke mice likely incorporating more edema than the lesion in ABCA1fl/fl stroke mice
The administration of HDL3 or ApoE2 into the ischemic brain of ABCA1-B/-B stroke mice starting 24 h and daily for 14 days significantly improve neurological functional outcome at 14 and 21 days after stroke (Figure 2B, p < 0.05, n = 9/group). These data show that the administration of HDL3 or ApoE2 into the ischemic brain of reverses ABCA1-B/-B induced functional deficit after stroke
Summary
Stroke is a major cause of white matter (WM) damage, which induces long-term disability due to the limited axonal regeneration and remyelination in the inhibitory environment of the adult mammalian central nervous system (CNS) [1–3]. WM refers to areas of the CNS that are mainly composed of bundles of axons ensheathed with myelin, i.e., myelinated axons [4,5]. WM damage including axonal degeneration and the loss of myelin known as demyelination induces the disturbance of messages passing between different areas of gray matter within the CNS, which may occur even in the early stage of brain impairment and evokes serious neurological functional deficits after stroke [4–6]. Oligodendrocytes (OLs), the unique myelin-forming cells in the CNS, ensheath axons with myelin and maintain long-term axonal integrity. Oligodendrogenesis plays an important role in the WM remodeling during brain repair [22]
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