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

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.

Figure 1.

Representative blood-to-brain uptake curves for L11.3 in CD-1 mice. All three regions showed a statistically significant uptake of L11.3. See Table 1 for Ki and statistical parameters.

Figure 2.

Clearance of antibody from blood. The highest values for %Inj/ml were found in 4 mo old SAMP8 mice given HyL5 and the lowest values in CD-1 mice given L11.3. All other clearance curves fell between these two curves.

Figure 3.

Comparison of antibodies and albumin. The brain/serum ratios for L11.3 (upper left panel), HyL5 (upper right panel), and control IgM antibody RF (lower left panel) were divided by the brain/serum ratios for simultaneously injected albumin. The lower right panel shows the brain/serum ratios for L11.3 divided by the brain/serum ratios for simultaneously injected HyL5. Data were collected 2h after the simultaneous iv injection of an antibody and albumin so that a ratio of greater than 1.0 indicates an uptake in excess of that for albumin. *indicates value different from the theoretical value of 1.0 at p<0.05 level.

Figure 4.

Upper panel shows a dose response curve for the effect of L11.3 given by intracerebroventricular administration on acquisition and retention in 12 mo old SAMP8 mice. Both acquisition and retention were improved (* = p<0.05;** = p<0.01) by the 24 and 240 ng dose of Ly11.3 when compared to administration to either the IgG or RF antibody controls. These doses were also significantly different from the 2.4 ng dose (p<0.05).

Figure 5.

Effect of iv L11.3 (25 microg/mouse) on acquisition and retention in 12 mo old SAMP8 mice. Acquisition, but not retention, was improved by L11.3. 4 mo old SAMP8 mice are shown for comparison.