The goal of this research program is to determine the role of amyloid plaque formation in the etiology of Alzheimer's disease. To be able to study the underlying mechanism(s) and to examine the consequences of beta- amyloid deposition, we are developing a small animal model of this pathological event. Transgenic mice have been generated which display extracellular beta-amyloid immunoreactive deposits in their brains. These deposits morphologically resemble several beta-amyloid immunoreactive structures observed in the brains of Alzheimer's disease victims. One research objective is to further characterize these transgenic mice as to similarity of their histopathology to the human condition. Possible age- dependent occurrence of beta-amyloid deposits, cytoskeletal alterations, abnormalities of neurotransmitter systems, and neuronal cell loss will be investigated using immunocytochemistry. Another objective of the research is to determine the mechanism of beta-amyloid formation by producing new transgenic mice. These new transgenic mice will be programmed to express exogenous beta-amyloid precursor genes similar to those used to produce the phenotype of beta-amyloid formation - except for specific coding sequence alterations. The mice expressing the mutated beta-amyloid precursor genes will be evaluated for beta-amyloid deposits again using immunocytochemistry. The resulting phenotypes of the new transgenic mice should further define the specific domains of the beta-amyloid precursor which are involved in amyloid formation. Both the development of a mouse model of Alzheimer's disease amyloidosis and the elucidation of the mechanism of amyloid formation may be useful in the identification of novel therapeutic agents designed to prevent beta-amyloid formation in individuals with this disease.
| Higgins, L S; Holtzman, D M; Rabin, J et al. (1994) Transgenic mouse brain histopathology resembles early Alzheimer's disease. Ann Neurol 35:598-607 |
