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2007 Grant - Mathews
Neuroprotection Following Modulation of Endogenous Beta-Amyloid in Mice
Paul M. Mathews, Ph.D.
New York University School of Medicine
Orangeburg, New York
2007 Investigator-Initiated Research Grant
One of the hallmarks of Alzheimer's disease is the accumulation in the brain of beta-amyloid, a tiny protein fragment suspected of disrupting cell-cell communication and damaging neurons. One promising therapeutic strategy for treating Alzheimer's disease is to use vaccination to rid the brain of this protein fragment. Two principle vaccination approaches are being pursued. One is to use a beta-amyloid "antigen" to stimulate the immune system to make antibodies that can bind to and remove beta-amyloid from the brain. The aim of the second approach, called "passive immunization," is the same, but beta-amyloid antibodies are administered directly.
Paul Matthews, Ph.D., and colleagues plan to study passive immunization in mouse models of Alzheimer's disease. They have made antibodies to mouse beta-amyloid and found that these help clear both mouse and human beta-amyloid from the brains of animals that produce both, even though the peptides are slightly different. This finding suggests that targeting a sub-population of beta-amyloid may be a feasible strategy for ridding the brain of all beta-amyloid. This may be important because toxic beta-amyloid exists in two major types, which can also bind together to form larger complexes, or aggregates. Matthews and colleagues will investigate if passive immunization helps clear those larger complexes from the brain.
The researchers will also use a similar strategy to study the pathology of Down syndrome, which is caused by a duplication of the chromosome that harbors the gene that codes for the beta-amyloid peptide. Most people with Down syndrome eventually develop Alzheimer-like pathology, even before beta-amyloid aggregates are apparent. The researchers will use a mouse model of Down syndrome to see if passive immunization can stem neurodegenera-tion. The studies will help show if passive immunization might be an effective strategy for treating Alzheimer's disease and Down syndrome-related dementia.