Reversible memory loss in a mouse transgenic model of Alzheimer's disease.
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.
Kotilinek
Linda A
LA
Department of Neurology, University of Minnesota, Minneapolis 55455, USA.
Bacskai
Brian
B
Westerman
Marcus
M
Kawarabayashi
Takeshi
T
Younkin
Linda
L
Hyman
Bradley T
BT
Younkin
Steven
S
Ashe
Karen H
KH
D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000150:complications / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry; D003071:Cognition / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D007116:Immunization, Passive / Q000379:methods; D007274:Injections, Intraperitoneal; D008297:Male; D008568:Memory / Q000187:drug effects; D008569:Memory Disorders / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D012074:Remission Induction / Q000379:methods; D013037:Spatial Behavior / Q000187:drug effects
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000911:Antibodies, Monoclonal