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Experimental Genetics Group
J Biol Chem, 1999 Mar 5;274(10):6483-6492. Moechars D1, Dewachter I1, Lorent K1, Reversé D4, Baekelandt V1, Naidu A2, Tesseur I1, Spittaels K1, Van Den Haute C1, Checler F3, Godaux E4, Cordell B1, Van Leuven F1. 1Experimental Genetics Group, Center for Human Genetics, Flemish Institute for Biotechnology, Katholieke Universiteit Leuven, Leuven, Belgium. 2Scios Inc., Sunnyvale, California. 3IPMC/CNRS, Valbonne, France. 4Laboratory of Neuroscience, University of Mons-Hainaut, Mons-Hainaut, Belgium. Transgenic mice overexpressing different forms of amyloid precursor protein (APP), i.e. wild type or clinical mutants, displayed an essentially comparable early phenotype in terms of behavior, differential glutamatergic responses, deficits in maintenance of long term potentiation, and premature death. The cognitive impairment, demonstrated in F1 hybrids of the different APP transgenic lines, was significantly different from nontransgenic littermates as early as 3 months of age. Biochemical analysis of secreted and membrane-bound APP, C-terminal "stubs," and Abeta(40) and Abeta(42) peptides in brain indicated that no single intermediate can be responsible for the complex of phenotypic dysfunctions. As expected, the Abeta(42) levels were most prominent in APP/London transgenic mice and correlated directly with the formation of amyloid plaques in older mice of this line. Plaques were associated with immunoreactivity for hyperphosphorylated tau, eventually signaling some form of tau pathology. In conclusion, the different APP transgenic mouse lines studied display cognitive deficits and phenotypic traits early in life that dissociated in time from the formation of amyloid plaques and will be good models for both early and late neuropathological and clinical aspects of Alzheimer's disease.  FULL TEXT |
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