Intrathecally infused antibodies against Nogo-A penetrate the CNS and downregulate the endogenous neurite growth inhibitor Nogo-A.
Neutralizing antibodies against the neurite growth inhibitory protein Nogo-A are known to induce regeneration, enhance compensatory growth, and enhance functional recovery. In intact adult rats and monkeys or spinal cord injured adult rats, antibodies reached the entire spinal cord and brain through the CSF circulation from intraventricular or intrathecal infusion sites. In the tissue, anti-Nogo antibodies were found inside Nogo-A expressing oligodendrocytes and neurons. Intracellularly, anti-Nogo-A antibodies were colocalized with endogenous Nogo-A in large organels, some of which containing the lysosomal marker cathepsin-D. This suggests antibody-induced internalization of cell surface Nogo-A. Total Nogo-A tissue levels in spinal cord were decreased in intact adult rats following 7 days of antibody infusion. This mechanism was confirmed in vitro; cultured oligodendrocytes and neurons had lower Nogo-A contents in the presence of anti-Nogo-A antibodies. These results demonstrate that antibodies against a CNS cell surface protein reach their antigen through the CSF and can induce its downregulation.
Weinmann
Oliver
O
Brain Research Institute, University of Zurich and Department Biology, ETH Zurich, Winterthurerstr. 190 8057 Zurich, Switzerland.
Schnell
Lisa
L
Ghosh
Arko
A
Montani
Laura
L
Wiessner
Christoph
C
Wannier
Thierry
T
Rouiller
Eric
E
Mir
Anis
A
Schwab
Martin E
ME
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D002555:Cerebrospinal Fluid / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004705:Endocytosis / Q000187:drug effects / Q000276:immunology; D005260:Female; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D007278:Injections, Spinal; D008252:Macaca fascicularis; D008297:Male; D009185:Myelin Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects / Q000276:immunology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D000070798:Nogo Proteins; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D013346:Subarachnoid Space / Q000378:metabolism
D000906:Antibodies; D006131:Growth Inhibitors; D009185:Myelin Proteins; D000070798:Nogo Proteins; C000603197:Rtn4 protein, rat