Intra- and extra-cellular cholesterol transport systems during brain repair and synaptic remodelling in the adult rodent brain

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Our team has documented an elegant mechanism by which the injured brain uses the cholesterol and phospholipids released from dead/dying cells to feed surviving neurons with the lipids which are required for the proper rebuilding new synaptic networks. We call this process the cholesterol recycling/remodeling cascade. Our team has already demonstrated that the extracellular transport of cholesterol and phospholipids by apolipoprotein E (apoE), a highly functional lipid transporter, is required and*necessary for the replacement of synaptic networks in response to brain injury or, neurotoxic insult in rodents. In response, cell-surface receptors that recognize apoE-lipoprotein complexes (i.e. HDL) were found to mediate the internalization and redistribution of the cholesterol required for the formation of new sprouts and new synapses. The complete absence of brain apoE or, its main receptor, in knockout mice was shown to compromise i) synaptic integrity with age, ii) lesion-induced synaptic recovery and iii) cognitive performance. Unfortunately, we know very little about the initiation of this cascade; i.e. the transport and packaging of cholesterol and phospholipids from intracellular astroglial compartments towards the apoE-lipoprotein (HDL) assembly line.***Cholesterol produced intracellularly is transported via a series of transporters called ATP-Binding cassette (ABC) complexes in both the periphery and in the CNS. The ABC transporters (ABCA and ABCG subclasses) are involved in the transport of phospholipids and/or cholesterol across the plasma membrane. A relationship between ABCG1 production and apoE*secretion has also been found in peripheral macrophages but not in the remodelling brain.****Hypothesis: In response to neuronal loss, brain cholesterol is mobilized primarily by astrocytes where the coordinated expression of ABCA1, A7 or G1 facilitates its movement toward the cell surface*where apolipoprotein E awaits to catalyze the transfer of lipids to apoE-rich HDL complexes.  These lipoproteins are subsequently used to feed neighboring neurons expressing apoE-receptors in need of large amount of lipids to rebuild synaptic networks and to expand existing ones.****Objectives: We propose to dissect the molecular cascade regulating cholesterol recycling by examining i) the intracellular transport of the lipids by the ABC transport system in glial cells both in vivo and in vitro, ii) the assembly of apoE-containing lipoprotein complexes in presence/absence of ABC transporters, iii) the interaction of apoE and ABCs with cell surface lipids and, iv) the binding and internalization of the apoE-HDL complex via lipoprotein receptors by neurons.***Expected Outcome: We believe that these studies will provide us with crucial insights as to the cascade of molecular events leading to the activation of synaptic repair and the delivery of key lipid species involved in brain repair*mechanisms.**