Cholesterol-related genes in response to brain deafferentation in normal and transgenic mice

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Our team has documented over the years an elegant mechanism by which the injured adult brain uses the cholesterol and phospholipids released from dead/dying cells to feed surviving neurons with the lipids required for the proper rebuilding local synaptic networks. We call this process the cholesterol recycling cascade. Our team has already demonstrated that the intra- and extracellular transport of cholesterol by apolipoprotein E (apoE) and ABCA1, highly functional lipid transporters, is required and necessary for the replacement of synaptic networks in response to brain injury in rodents. In response, neuronal cell-surface receptors belonging to the LDL receptors family that recognize apoE-lipoprotein complexes mediate the internalization of the HDL-cholesterol used in the formation of new synapses. The complete absence of brain apoE or, of its main receptor, in knockout mice was shown to compromise i) synaptic integrity with aging, ii) lesion-induced synaptic recovery and iii) cognitive performance. We know very little about the triggering and regulating mechanisms controlling this cascade; i.e. the transport and packaging of cholesterol and phospholipids from the astroglial compartments toward the apoE-lipoprotein (HDL) assembly line, and the final LDL receptor (LDLR)-mediated internalisation. We know that certain ATP-Binding Cassette (ABC) proteins such as A1 are involved, facilitating the transfer of lipids to HDLs at the surface.  Hypothesis: In response to neuronal loss, brain cholesterol is mobilized 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 the lipids to extracellular apoE-rich HDL complexes. These lipid-enriched lipoproteins are subsequently used to feed neighboring neurons via the LDL receptors family which are tightly regulated by the presence of the so-called of SREBF2 and PCSK9 proteins; one is a potent activator of LDL receptor production (SREBF2) while the other (PCSK9) facilitate the LDLR elimination and catabolism. Subsequently, large amounts of lipids are engulfed by surviving neurons and are used to rebuild new dentritic and synaptic networks. Objectives: We propose to dissect the molecular cascade regulating the cholesterol recycling process by examining i) the intracellular transport of the lipids by the ABC transport system in glial cells in vivo during deafferentation and reinnervation, ii) the assembly of apoE-lipoprotein complexes in presence/absence of ABCA7 and LDLR in lesioned mice,  iii) the interaction of apoE and ABCs with cell surface lipids and, iv) the binding and internalization of the apoE-HDL complex via the LDL receptors by neurons. Expected Outcome: We believe that these studies will provide crucial insights in regard to the molecular events leading to the activation of synaptic repair and the delivery of key lipid species during brain repair in the adult rodent brain.