Using doxycycline to control the onset of transgenic APP expression. The tet-off APP model uses TTA expressed from the CaMKIIα promoter to control the expression of mutant APP. Under normal conditions, expression from this promoter begins during late embryogenesis and transgenic APP is present at high levels by birth (juvenile onset). Transgene expression can be delayed by rearing the mice on dox, initially transmitted to the pups through their mother’s milk. Dox treatment was used to suppress transgenic APP beginning from shortly after birth (P1-P3) until adulthood (P41-P43). Transgenic APP expression was initiated at 6 wk of age by removing dox from the diet (adult onset). In both sets of mice, bigenic (APP/TTA) and control (TTA) animals were behaviorally evaluated following 7 wk or 4 mo of transgene expression, and again after 1 mo of therapeutic dox treatment to suppress APP expression after the formation of amyloid plaques (grey arrowheads). Adult-onset animals were additionally evaluated immediately after removing dox (0 wk of APP expression), and 1 wk later (1 wk of APP expression) to assess the impact of overproducing APP in the absence of Aβ accumulation. Behavioral testing at equivalent time points (P0 and P7) was not possible in the juvenile-onset animals.