Behavioral disturbances without amyloid deposits in mice overexpressing human amyloid precursor protein with Flemish (A692G) or Dutch (E693Q) mutation

The contribution of mutations in the amyloid precursor protein (APP) gene k nown as Flemish (APP/A692G) and Dutch (APP/E693Q) to the pathogenesis of Al zheimer's disease and hereditary cerebral hemorrhage with amyloidosis of th e Dutch type, respectively, was studied in transgenic mice that overexpress the mutant APP in brain. These transgenic mice showed the same early behav ioral disturbances and defects and increased premature death as the APP/Lon don (APP V7171), APP/ Swedish (K670N, M671L), and other APP transgenic mice described previously. Pathological changes included intense glial reaction , extensive microspongiosis in the white matter, and apoptotic neurons in s elect areas of the brain, while amyloid deposits were absent, even in mice over 18 months of age. This contrasts with extensive amyloid deposition in APP/London transgenic mice and less pronounced amyloid deposition in APP/Sw edish transgenic mice generated identically. It demonstrated, however, that the behavioral deficiencies and the pathological changes in brain resultin g from an impaired neuronal function are caused directly by APP or its prot eolytic derivative(s). These accelerate or impinge on the normal process of aging and amyloid deposits per se are not essential for this phenotype. (C ) 2000 Academic Press.