ABCA1 regulates white matter remodeling and oligodendrogenesis after stroke

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 DESCRIPTION (provided by applicant): Stroke is a major cause of white matter (WM) damage which induces long-term disability. There is limited WM- remodeling in the adult brain. Many neuroprotective treatments of stroke have failed in clinical trials because they cannot protect WM. Therefore, there is a compelling need to investigate the mechanism underlying WM- remodeling and oligodendrogenesis of the adult brain and to develop effective long-term stroke therapy. Cellular cholesterol modulates axonal and dendritic outgrowth and is required for myelination. The level of HDL-cholesterol is related to the progression and recovery of stroke patients. ATP-binding cassette transporter A 1 (ABCA1) is a major cholesterol transporter and plays critical roles in regulation of HDL-cholesterol and ApoE synthesis and metabolism in the central nervous system. Brain specific-ABCA1 deficient (ABCA1-B/-B) mice have very low brain HDL-cholesterol/ApoE level, and exhibit neuronal ultrastructure changes and functional deficits. Both HDL-cholesterol and ApoE increase neurite outgrowth in culture conditions. Our preliminary study shows that ABCA1-B/-B mice exhibited increased WM damage and reduced oligodendrogenesis and exacerbated neurological functional deficits after stroke. Primary cultured neurons derived from ABCA1-B/-B mice show decreased neurite outgrowth, which can be attenuated by HDL treatment. ABCA1-B/-B astrocyte-conditioned media also decreased wild type neurite outgrowth after hypoxic ischemia. Therefore, we propose the following three specific aims: Aim1 To investigate whether brain-deficient in ABCA1 exhibits decreases in WM-remodeling and axonal growth after stroke. ABCA1 -B/-B and floxed-control mice will be subjected to stroke, WM-changes and oligodendrogenesis will be measured. Aim2 To investigate molecular mechanism underlying ABCA1 in regulation of WM-remodeling and oligodendrogenesis after stroke, we will examine whether ABCA1 regulates brain HDL and ApoE level, and whether brain HDL and ApoE levels mediate ABCA1-induced WM-remodeling and oligodendrogenesis after stroke. Aim3 To investigate cellular mechanisms of ABCA1 in regulation of WM-remodeling and oligodendrogenesis, we will examine neurons and oligodendrocytes and the cross talk of astrocytes with neurons and oligodendrocytes on ABCA1-induced WM- remodeling and oligodendrogenesis in vitro and in vivo. We expect that ABCA1 deficient brain will exhibit significant decreases in HDL and ApoE level, and decreases WM-remodeling and oligodendrogenesis as well as reduced functional outcome after stroke. The level of HDL/ApoE in brain or cerebrospinal fluid will, at least partially, mediate ABCA1-induced WM-remodeling and oligodendrogenesis in the ischemic brain after stroke. To our knowledge, no one has investigated the functional effect of ABCA1 on oligodendrogenesis and WM- remodeling post-stroke recovery, especially by using ABCA1-B/-B mice. The new insights gleaned from this study will contribute to our understanding of the beneficial role of ABCA1/HDL-C/ApoE in brain plasticity which will impact development of rational restorative approaches to improve neurological outcome for stroke patients.