Lack of β-Amyloidosis in transgenic mice expressing low levels of familial Alzheimerʹs disease missense mutations

Point mutations within the β-amyloid precusor protein (β-APP) gene known to segregate with Alzheimerʹs disease in certain families were introduced into human β-APP cDNAs and expressed under the control of a neuron-specific enolase (NSE) promoter in mice. The transgenic animals exhibited transgene expression predominantly in neocortex and hippocampus where the levels were maximally 1.3-fold of those of wild-type mouse β-APP. Quantitative immunoblot analysis in homozygous mice carrying different missense mutations showed slightly increased α-secretory processing. In V717I mice compared to nontransgenic mice there was more α-secretory β-APP (β-APPsec) in cortex/hippocampus, less in cerebellum, and no difference in midbrain/brain stem. In none of the transgenic animals tested was a 4 kDa amyloid fragment detected by Western blotting of brain extracts, immunohistochemistry, or by 125I-Aβ-binding onto brain sections. No glial reaction was observed. Behavioral analysis of mice carrying the V717I mutation showed no appreciable deficit in comparison to wild-type mice. Together, these data suggest that low levels of expression of mutated β-APP in 10–12-month-old transgenic mouse brains result in slightly more β-APPsec, and are insufficient to induce amyloidogenic processing and AD-like pathology.