Enhanced CNS uptake of systemically administered proteins through conjugation with tetanus C-fragment

Paul S. Fishman, Joseph M. Savitt, Dawn A. Farrand

Research output: Contribution to journalArticlepeer-review

Abstract

No other exogenous protein enters the central nervous system from the circulation as readily as tetanus toxin. We examined the capability of the non-toxic binding fragment of tetanus toxin (C-Fragment) so serve as a vehicle for transport of other proteins into the mouse CNS. Using periodate oxidation of the enzyme horseradish peroxidase (HRP), we synthesized two separate macromolecular complexes, one containing C-fragment and HRP, and the other C-fragment, HRP and a third "test" protein-human IgG. The distribution of C-fragment-HRP was typical of blood borne proteins including native C-fragment, with labeling of all neurons with known projections outside the blood-brain barrier, particularly large spinal motoneurons. C-fragment-HRP conjugates showed superior neuronal labeling to over 100-fold greater quantities of free HRP. Complexes containing C-fragment, HRP and human IgG were internalized by neurons from both intramuscular and intraperitoneal injections. The efficiency of neuronal uptake of IgG in the C-fragment conjugated form was enhanced over 40-fold compared to free IgG. Linkage of a large protein to C-fragment probably leads to enhanced endocytosis of that protein by neuronal terminals projecting outside the blood-brain barrier. C-fragment can serve as a vehicle to allow selected proteins to bypass the barrier and enter the CNS.

Original languageEnglish (US)
Pages (from-to)311-325
Number of pages15
JournalJournal of the Neurological Sciences
Volume98
Issue number2-3
DOIs
StatePublished - Sep 1990
Externally publishedYes

Keywords

  • Axonal transport
  • Blood-brain barrier
  • C-fragment
  • Endocytosis
  • Horseradish peroxidase
  • Motoneurons
  • Tetanus toxin

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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