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Role of LSR in the regulation of cholesterol homeostasis in the central nervous system

Abstract : Cholesterol is a crucial lipid in the central nervous system (CNS) and its strict regulation ensures proper neuronal development and function. Cholesterol is synthesized in the CNS by glial cells which produce and secrete cholesterol to meet neuronal needs. Lipoproteins and their receptors are key elements of this intercellular transport: where the latter recognize, bind and endocytose lipoproteins containing cholesterol. The lipolysis stimulated lipoprotein receptor (LSR) is the most recently discovered receptor in the CNS. It is a multimeric protein complex that undergoes conformational changes during the binding of free fatty acids, thus revealing a binding site which recognizes apolipoproteins B and E. Complete inactivation of the LSR gene is lethal at embryonic level, probably due to a leaky blood brain barrier. In addition, studies in LSR +/- mice have revealed a change in the distribution of cholesterol and cognitive functions. Our first goal was to perform LSR profiling at the tissue and cell level. Our results revealed a differential expression of the LSR subunits. In vitro studies in primary cell cultures have shown that LSR is highly expressed in different regions of the CNS, both in glial and neuronal cells. Our hypothesis was that a strong expression of LSR in glial cells could play a role in controlling the synthesis of cholesterol, by limiting the cholesterol circulating in the extracellular fluid of the brain. To verify this hypothesis, we have developed an inducible Cre-lox system specifically targeting glial cells. Behavioral phenotyping demonstrated a deficit in olfactory function which has an impact on the social memory of these animals. Although no visual problems were detected, the object recognition test showed that the visual memory was affected. Additionally, Y and Barnes mazes tests revealed an impacted short- and long-term memory. Our results suggest that specific inactivation of LSR in glial cells impairs animal memory, affecting spatial and social memory. Interestingly and similarly to AD, the early signs monitored olfactory deficits. Using a strategy combining behavioral phenotyping, immunostaining and biochemical analysis of specific markers of synaptic plasticity, this model could also be used to determine the role of LSR in brain cognition and cholesterol trafficking in the CNS, and could provide the means to validate LSR as a potential therapeutic target for the treatment of damage caused by lipid storage and the development of neurodegenerative diseases in the aging brain.
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Aseel El Hajj. Role of LSR in the regulation of cholesterol homeostasis in the central nervous system. Agronomy. Université de Lorraine, 2019. English. ⟨NNT : 2019LORR0317⟩. ⟨tel-02863260⟩

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