Abstract
The regulation of cholesterol, an essential brain lipid, ensures proper neuronal development and function, as demonstrated by links between perturbations of cholesterol metabolism and neurodegenerative diseases, including Alzheimer’s disease. The central nervous system (CNS) acquires cholesterol via de novo synthesis, where glial cells provide cholesterol to neurons. Both lipoproteins and lipoprotein receptors are key elements in this intercellular transport, where the latter recognize, bind and endocytose cholesterol containing glia-produced lipoproteins. CNS lipoprotein receptors are like those in the periphery, among which include the ApoB, E binding lipolysis stimulated lipoprotein receptor (LSR). LSR is a multimeric protein complex that has multiple isoforms including α and α’, which are seen as a doublet at 68 kDa, and β at 56 kDa. While complete inactivation of murine lsr gene is embryonic lethal, studies on lsr +/- mice revealed altered brain cholesterol distribution and cognitive functions. In the present study, LSR profiling in different CNS regions revealed regiospecific expression of LSR at both RNA and protein levels. At the RNA level, the hippocampus, hypothalamus, cerebellum, and olfactory bulb, all showed high levels of total lsr compared to whole brain tissues, whereas at the protein level, only the hypothalamus, olfactory bulb, and retina showed the highest levels of total LSR. Interestingly, major regional changes in LSR expression were observed in aged mice which suggests changes in cholesterol homeostasis in specific structures in the aging brain. Immunocytostaining of primary cultures of mature murine neurons and glial cells isolated from different CNS regions showed that LSR is expressed in both neurons and glial cells. However, lsr RNA expression in the cerebellum was predominantly higher in glial cells, which was confirmed by the immunocytostaining profile of cerebellar neurons and glia. Based on this observation, we would propose that LSR in glial cells may play a key role in glia-neuron cross talk, particularly in the feedback control of cholesterol synthesis to avoid cholesterol overload in neurons and to maintain proper functioning of the brain throughout life.
Highlights
Cholesterol is essential for neuronal physiology; a tight regulation of cholesterol homeostasis in the central nervous system (CNS) is essential for proper neuronal development and function
A series of lipoprotein receptors expressed in neurons have been identified including the low density lipoprotein receptor (LDL-R) [8], low density lipoprotein receptor-related protein 1 (LRP-1) [8], and lipolysis stimulated lipoprotein receptor (LSR) [9]
Immunoblots show that the HT, olfactory bulb (OB), and RET express the highest levels of LSR when normalized to β-tubulin III (β-TUB), which may reflect a specific need of these regions to tightly regulate cholesterol for proper functioning
Summary
Cholesterol is essential for neuronal physiology; a tight regulation of cholesterol homeostasis in the central nervous system (CNS) is essential for proper neuronal development and function. Daneman’s laboratory identified the presence of lsr gene transcript in endothelial cells (ECs) of the BBB [17] and showed that LSR is a component of paracellular junctions highly enriched in the BBB ECs, but not in ECs in peripheral tissues outside the CNS [15]. Another study reported the high expression of LSR in tricellular junctions, in the BBB, and in retinal ECs that form the inner blood retinal barrier (BRB) [18] This indicates that LSR plays a critical role in maintaining the BBB integrity and suggests a potential role of LSR in the transport of lipoproteins between the brain parenchyma and the CSF. This study revealed differential expression of LSR isoforms in different regions, which would help us, in the future, understand the possible role of LSR in the cholesterol crosstalk between glial cells and neurons
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