Reversible memory loss in a mouse transgenic model of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative condition, believed to be irreversible, characterized by inexorable deterioration of memory and intellect, with neuronal loss accompanying amyloid plaques and neurofibrillary tangles. In an amyloid precursor protein transgenic mouse model, Tg2576, little or no neuronal loss accompanies age-related memory impairment or the accumulation of Abeta, a 40-42 aa polypeptide found in plaques. Recently, we have shown inverse correlations between brain Abeta and memory in Tg2576 mice stratified by age (Westerman et al., 2002). Broadening the age range examined obscured this relationship, leading us to propose that small, soluble assemblies of Abeta disrupt cognitive function in these mice. Here we show that memory loss can be fully reversed in Tg2576 mice using intraperitoneally administered BAM-10, a monoclonal antibody recognizing the N terminus of Abeta. The beneficial effect of BAM-10 was not associated with a significant Abeta reduction, but instead eliminated the inverse relationship between brain Abeta and memory. We postulate that BAM-10 acts by neutralizing Abeta assemblies in the brain that impair cognitive function. Our results indicate that a substantial portion of memory loss in Tg2576 mice is not permanent. If these Abeta assemblies contribute significantly to memory loss in AD, then successfully targeting them might improve memory in some AD patients.

Fig. 1.

Longitudinal experimental design using Tg2576 mice to determine whether memory loss, once present, can be restored. Spatial reference memory was measured, using the Morris water maze (Morris, 1984), immediately before and after intraperitoneal administration of BAM-10, a monoclonal antibody recognizing the N terminus of Aβ.

Fig. 2.

Spatial reference learning and memory in 9- to 11-month-old Tg2576 mice before and after treatment with BAM-10 antibody. The change in retention of spatial memory occurring as a result of receiving BAM-10 or IgG antibodies intraperitoneally was measured by subtracting baseline scores from post-treatment scores to obtain the change in percentage of time spent in the target quadrant (Change in %-time).a, Mice 9–11 months of age receiving BAM-10 antibody showed significantly greater improvement than mice receiving nonspecific IgG (*p = 0.03 by ttest; IgG, n = 17; BAM-10, n = 16). b, In mice that were impaired at baseline (<40% of the time spent in the target quadrant), those receiving BAM-10 antibody also showed significantly greater improvement than those receiving nonspecific IgG (*p = 0.04 by two-way ANOVA with repeated measures; IgG, n = 13; BAM-10,n = 14). Post-treatment performance of impaired mice receiving BAM-10 antibody was significantly higher than baseline performance (*p = 0.01 by paired ttest) and was similar to that of 2-month-old Tg2576 mice (n = 17) and 3-month-old nontransgenic littermates (n = 10). c, BAM-10, but not nonspecific IgG, restored the retention learning curve of 9- to 11-month-old Tg2576 mice to resemble that of 2-month-old (Young) Tg2576 mice. d, Acquisition of spatial reference memory improved in impaired mice receiving BAM-10 antibody, with significantly reduced mean escape latencies on days 3–5 (*p = 0.04 by paired t test), but not in mice receiving nonspecific IgG. There was a significant treatment-by-training session (baseline vs post-treatment) interaction (p = 0.03 by two-way ANOVA with repeated measures).

Fig. 3.

Aβ levels in Tg2576 mice treated with BAM-10 or nonspecific IgG antibody. Total Aβ is the sum of Aβ40 and Aβ42 in TBS, 2% SDS, and formic acid (FA) soluble fractions measured as described previously (Kawarabayashi et al., 2001). a, Treatment of mice with BAM-10 was not associated with a significant reduction in total Aβ or in Aβ40 or Aβ42 in any of the fractions analyzed (p values ranged from 0.2 to 0.9). Measurements represent means ± SDs. Brain Aβ levels were correlated with memory in 8.7-month-old Tg2576 mice treated with BAM-10 or nonspecific IgG antibody. b, There was a significant inverse correlation between total Aβ and probe scores in control mice treated with nonspecific IgG.c, Treatment with BAM-10 eliminated the correlation between total Aβ and probe scores.

Fig. 4.

BAM-10 neutralizes the cognitively disruptive activity of small Aβ assemblies in the brain. Top, Memory loss in Tg2576 mice appears to be caused by small Aβ assemblies (stars) (Westerman et al., 2002) formed during the conversion of Aβ monomers (circles) to amyloid deposits (starbursts). Aging refers to the event or series of events occurring as animals age leading to the initial aggregation of monomeric Aβ. Little is known about what comprises these events. Bottom, BAM-10 penetrates into the brain, where it may bind to these small Aβ assemblies, neutralize their deleterious effects on cognitive function, and rapidly restore memory in Tg2576 mice. With prolonged treatment, a reduction in amyloid deposits may occur.