Anti-amyloid Beta Protein Antibody Passage Across the Blood-Brain Barrier in the SAMP8 Mouse Model of Alzheimer's Disease: An Age-Related Selective Uptake With Reversal of Learning Impairment

Exp Neurol. 2007 Aug;206(2):248-56. doi: 10.1016/j.expneurol.2007.05.005. Epub 2007 May 22.

Abstract

Amyloid beta protein (Abeta) levels are elevated in the brain of Alzheimer's disease patients. Anti-Abeta antibodies can reverse the histologic and cognitive impairments in mice which overexpress Abeta. Passive immunization appears safer than vaccination and treatment of patients will likely require human rather than xenogenic antibodies. Effective treatment will likely require antibody to cross the blood-brain barrier (BBB). Unfortunately, antibodies typically cross the BBB very poorly and accumulate less well in brain than even albumin, a substance nearly totally excluded from the brain. We compared the ability of two anti-Abeta human monoclonal IgM antibodies, L11.3 and HyL5, to cross the BBB of young CD-1 mice to that of young and aged SAMP8 mice. The SAMP8 mouse has a spontaneous mutation that induces an age-related, Abeta-dependent cognitive deficit. There was preferential uptake of intravenously administered L11.3 in comparison to HyL5, albumin, and a control human monoclonal IgM (RF), especially by hippocampus and olfactory bulb in aged SAMP8 mice. Injection of L11.3 into the brains of aged SAMP8 mice reversed both learning and memory impairments in aged SAMP8 mice, whereas IgG and IgM controls were ineffective. Pharmacokinetic analysis predicted that an intravenous dose 1000 times higher than the brain injection dose would reverse cognitive impairments. This predicted intravenous dose reversed the impairment in learning, but not memory, in aged SAMP8 mice. In conclusion, an IgM antibody was produced that crosses the BBB to reverse cognitive impairment in a murine model of Alzheimer's disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aging / immunology*
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / immunology
  • Alzheimer Disease / physiopathology
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / immunology
  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / metabolism
  • Antibodies, Monoclonal / pharmacokinetics*
  • Blood-Brain Barrier / drug effects*
  • Blood-Brain Barrier / immunology
  • Brain / drug effects
  • Brain / immunology
  • Brain / physiopathology
  • Cell Line, Transformed
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Immunoglobulin M / immunology
  • Immunoglobulin M / metabolism
  • Immunoglobulin M / pharmacology
  • Immunoglobulins, Intravenous / immunology
  • Immunoglobulins, Intravenous / pharmacokinetics
  • Immunoglobulins, Intravenous / therapeutic use
  • Injections, Intravenous
  • Learning Disabilities / drug therapy*
  • Learning Disabilities / genetics
  • Learning Disabilities / immunology
  • Mice
  • Mice, Neurologic Mutants
  • Mutation / genetics
  • Treatment Outcome

Substances

  • Amyloid beta-Peptides
  • Antibodies, Monoclonal
  • Immunoglobulin M
  • Immunoglobulins, Intravenous