Title: Expression and Functions of LRP-2 in Central Nervous System: Progress in Understanding its Regulation and the Potential Use for Treatment of Neurodegenerative Diseases
Volume: 10
Issue: 4
Author(s): Carlos Spuch and Carmen Navarro
Affiliation:
Keywords:
Alzheimer's disease, astrocytes, brain, central nervous system, LRP-2, megalin, neuron and neurodegenerative diseases, neuron, glycoprotein, lysosomes, receptors, ligands, (IGF)-I, ApoE, ICD-LRP-2, proteolysis, LDLR, VLDL-R, LRP1, LRP1B, PSD95, SEMCAP-1, metalloproteinase, glomerulus, thyroid, pneumocytes, oxidation, homeostasis, transcytosis, proteins, blastocysts, ectoderm, neuroectoderm, phenotype, neurons, Purkinje cells, Signal Transduction, lipoproteins, APP, metallothionein, apoptosis, genotype, TUNEL-positive neurons, amyloid beta, malignant, Regulated intramembrane proteolysis, Src homology
Abstract: Lipoprotein related protein (LRP)-2 is a class of single transmembrane glycoprotein, generally recognized as cell surface endocytic receptors, which binds and internalizes extracellular ligands for degradation in lysosomes. LRP-2 is a multi-ligand endocytic receptor expressed in the choroid plexus epithelium, brain-endothelial cells, astrocytes, spinal cord, and retinal ganglion cells, and widely distributed in neurons through the brain. In the blood-brain-barrier LRP-2 plays a central role in the clearance/entrance of many proteins from the brain/cerebrospinal fluid. It has already been implicated in amyloid-β clearance and amyloidosis through the blood brain barrier. Also, it is a promiscuous receptor involved in the endocytic uptake of dozens of ligands, including many of the known carriers of amyloid-beta, insulin, insulin-like growth factor (IGF)-I, leptin, transthyretin, transferrin, apolipoprotein E (ApoE) and other molecules regulating the environment of the brain. LRP-2 immunoreactivity was also localized in neurons in different stages, suggesting that LRP-2 is implicated in signal transduction during embryonic development, neuronal outgrowth or in the pathogenesis of neurodegenerative diseases such as Alzheimers disease. Recently, information regarding the structural and functional elements within their cytoplasmic tail has begun to emerge, which suggests that LRP-2 is working not only in receptor mediated endocytosis, but also in transducing signals into the cytoplasm. It was reported that LRP-2 is subjected to regulated intramembrane proteolysis producing a soluble extracellular fragment and LRP-2 intracellular domain (ICD-LRP-2). Based on similar studies with other receptors, the ICD-LRP-2 is predicted to target to the nucleus and regulate gene expression. These findings suggest that LRP-2 has a crucial role in development of central nervous system, regulation of transcription factors, neuronal outgrowth and regulation of signal transducing pathways in the neuron. This review will discuss the new facts about the knowledge of LRP-2 in the central nervous system in healthy and also different pathological situations.
