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.
Stroke induced white matter damage is associated with long-term disability due to the limited white matter remodeling in the adult brain. We will investigate major cholesterol transporter (ABCA1), high density lipoprotein (HDL), apolipoprotein E (ApoE) and cholesterol signaling activity in white matter remodeling and functional recovery after stroke by using a rodent stroke model and neural cell culture model. Our studies will provide novel insights into the mechanism research of brain restoration after stroke injury and may set the stage for development of a novel restorative therapy for clinical stroke.
