title: Peptide derived from HIV-1 TAT protein destabilizes a monolayer of endothelial cells in an in vitro model of the blood-brain barrier and allows permeation of high molecular weight proteins.
abstract: Most chemotherapeutic agents are blood-brain barrier (BBB) impermeants. HIV-1-derived TAT protein variants contain a transmembrane domain, which may enable them to cross the BBB and reach the brain. Here we synthesized CAYGRKKRRQRRR, a peptide containing a cysteine moiety attached to the N terminus of the transmembrane domain (C-TAT peptide), and studied its effects in an in vitro BBB model, which we found to reflect penetration by a receptor-independent pathway. Incubation of the brain capillary endothelial cell monolayer with 0.3-0.6 μmol/ml of this C-TAT peptide, for a period of 1-2 h, destabilizes brain capillary endothelial cell monolayer and introduces the ability of impermeant therapeutic agents including high molecular weight proteins to penetrate it substantially. The cysteinyl moiety at position 1 of the C-TAT peptide contributes largely to the destabilizing potency and the penetration efficacy of impermeant substances. The destabilizing effect was reversed using heparin. In summary, experimental conditions allowing a significant increase in entry of impermeant low and high molecular weight substances from the luminal (blood) to the abluminal side (brain) were found in an in vitro BBB model reflecting in vivo protein penetrability by a receptor-independent pathway.
authors.affiliation: Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel. itzik.cooper@sheba.health.gov.il
authors.forename: Itzik
authors.initials: I
authors.lastname: Cooper
authors.forename: Keren
authors.initials: K
authors.lastname: Sasson
authors.forename: Vivian I
authors.initials: VI
authors.lastname: Teichberg
authors.forename: Michal
authors.initials: M
authors.lastname: Schnaider-Beeri
authors.forename: Mati
authors.initials: M
authors.lastname: Fridkin
authors.forename: Yoram
authors.initials: Y
authors.lastname: Shechter
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D015658:HIV Infections / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D008970:Molecular Weight; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D010539:Permeability; D021381:Protein Transport; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D013552:Swine; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D010455:Peptides; D011506:Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus