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Experimental Genetics Group

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

Neurobiol Dis, 2000 Feb;7(1):9-22.

Kumar-Singh S1,8, Dewachter I2,8, Moechars D3, Lübke U4, De Jonghe C1, Ceuterick C5, Checler F6, Naidu A7, Cordell B7, Cras P4, Van Broeckhoven C1, Van Leuven F1.

1Flanders Interuniversity Institute for Biotechnology, Born-Bunge Foundation, Department of Biochemistry, University of Antwerp, Antwerp, Belgium.
2Laboratory of Neurobiology, Born-Bounge Foundation, Department of Medicine, University of Antwerp, Antwerp, Belgium.
3Laboratory of Electronmicroscopy, Born-Bunge Foundation, Department of Medicine, University of Antwerp, Antwerp, Belgium.
4Experimental Genetics Group, Center for Human Genetics, Flanders Interuniversity Institute for Biotechnology, K.U.Leuven, Leuven, Belgium.
5Department of Functional Genomics, Janssen Research Foundation, Beerse, Belgium.
6 Institut de Pharmacologie Moleculaire et Cellulaire, Valbonne, France.
7Scios Inc., Sunnyvale, California.
8These authors contributed equally to this work.

The contribution of mutations in the amyloid precursor protein (APP) gene known as Flemish (APP/A692G) and Dutch (APP/E693Q) to the pathogenesis of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis of the Dutch type, respectively, was studied in transgenic mice that overexpress the mutant APP in brain. These transgenic mice showed the same early behavioral disturbances and defects and increased premature death as the APP/London (APP V717I), 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 select 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/Swedish transgenic mice generated identically. It demonstrated, however, that the behavioral deficiencies and the pathological changes in brain resulting from an impaired neuronal function are caused directly by APP or its proteolytic derivative(s). These accelerate or impinge on the normal process of aging and amyloid deposits per se are not essential for this phenotype.

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