Transport Mechanisms at the Blood-Cerebrospinal-Fluid Barrier: Role of Megalin (LRP2)
The central nervous system (CNS) barriers are composed of blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (B-CSFB). The BBB and B-CSFB are a highly specialized brain endothelial and epithelial structure of the fully differentiated neurovascular system. These barriers separate components of the circulating blood from neurons. Moreover, the BBB and B-CSFB maintain the chemical composition of the neuronal “milieu,” which is required for the proper functioning of neuronal circuits, synaptic transmission, synaptic remodelling, angiogenesis, and neurogenesis in the adult brain. Hematoencephalic barrier breakdown, due to disruption of the tight junctions, alters transport of molecules between blood and brain and vice versa, causes an aberrant angiogenesis, vessel regression, and inflammatory responses. Megalin is a multi-ligand endocytic receptor expressed in the choroid plexus epithelium and in the brain-endothelial cells, playing a central role in the clearance/entrance of many proteins from the brain or cerebrospinal fluid (CSF). Megalin cooperates with various membrane molecules and interacts with many adaptor proteins for endocytic trafficking. It has already been implicated in amyloid-β clearance and amyloidosis through the BBB and B-CSFB. Also, it is a promiscuous receptor involved in the endocytic uptake of many ligands, including many of the known carriers of amyloid-β, insulin, IGF-I, leptin, transthyretin, transferrin, ApoE and others. The knowledge of B-CSFB and its transporters in healthy and pathological situations supports the development of new therapeutic approaches for chronic diseases such as Alzheimers, Parkinsons, amyotrophic lateral sclerosis, multiple sclerosis, brain cancer, diabetes and others. This article outlines recent patents on artificial carriers for transport of substances across of the CNS barriers, different models for the drug delivery research and future therapies for the treatment of Alzheimers disease.
Keywords: Amyloid, Alzheimer's disease, blood-CSF barrier, blood-brain barrier, clearance, drug delivery, IGF, LRP-1, LRP-2, megalin, milieu, transthyretin, amyloidosis, choroid plexus epithelial cells, clathrin-coated pits, cerebrovascular endothelial cells, choroid plexus epithelium, arachnoid epithelium, claudins, occludins, cingulin, pino-cytic vesicles, pericytes, apical surface, astrocytes, Apolipoprotein E receptors type-2, very low-density lipoprotein receptor, LDL-R-related protein 1, FXNPXY sequences, mitogen-activating protein, kinase scaffold proteins, c-Jun N-terminal kinase -interacting protein, synaptic density protein-95, semaphorin-binding protein-1, disabled homolog, (Dab)-1, Dab2, autosomal recessive hypercholesterolemia, regulated intramembrane proteolysis, metallo-proteinase, presenilin 1, Notch, p75NTR signalling pathway, membrane-associated C-terminal fragment, MCTF, intracellular domain
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