Journal
EXPERIMENTAL NEUROLOGY
Volume 206, Issue 2, Pages 248-256Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2007.05.005
Keywords
Alzheimer's disease; amyloid beta protein; therapeutics; monoclonal antibody; blood-brain barrier; IgM; passive immunization; cognition
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Funding
- NIA NIH HHS [R01 AG029839] Funding Source: Medline
- NINDS NIH HHS [R01 NS051334-01A1, R01NS050547, R01NS051334, R01 NS050547, R01 NS051334, R01 NS050547-01A2] Funding Source: Medline
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Amyloid beta protein (A beta) levels are elevated in the brain of Alzheimer's disease patients. Anti-A antibodies can reverse the histologic and cognitive impairments in mice which overexpress A beta. 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-A beta human monoclonal IgM antibodies, L 11.3 and HyL5, to cross the BBB of young CD-I mice to that of young and aged SAMP8 mice. The SAMP8 mouse has a spontaneous mutation that induces an age-related, A beta-dependent cognitive deficit. There was preferential uptake of intravenously administered L 11.3 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. (c) 2007 Elsevier Inc. All rights reserved.
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