Over-expression of two different forms of the α-secretase ADAM10 affects learning and memory in mice

Members of the ADAM family (a disintegrin and metalloprotease) are the main candidates for physiologically relevant alpha-secretases. The alpha-secretase cleaves in the non-amyloidogenic pathway the amyloid precursor protein within the region of the A beta peptides preventing their aggregation in the brain. The increase of a-secretase activity in the brain provides a plausible strategy to prevent A beta formation. Concerning this possibility two transgenic mouse lines (FVB/N) have been created: mice over-expressing the bovine form of the alpha-secretase (ADAM10) and mice over-expressing an inactive form of the a-secretase (ADAM10-E348A-HA; ADAM 10-dn). For behavioral examination a F1 generation of transgenic mice (C57B1/6 x FVB/N (tg)) was generated and compared to wild type F1 generation (C57B1/6 x FVB/N). Behavior was characterized in the following tasks: standard open field, enriched open field, elevated plus-maze, and the Morris water maze hidden platform task. Concerning basal activity, exploration, and anxiety, transgenic mice behaved similar to controls. With respect to learning and memory both transgenic lines showed a significant deficit compared to controls. ADAM10 mice however, showed thigmotaxis with passive floating behavior in the Morris water maze indicating differences in motivation, whereas, ADAM10-dn mice displayed an inconspicuous but limited goal-directed search pattern. Thus variation of the enzymatic activity of a-secretase ADAM10 alters learning and memory differentially. Nevertheless, it could be concluded that both, ADAM10 and ADAM10-dn mice are suitable control mice for the assessment of a-secretase-related effects in animal models of Alzheimer's disease. (c) 2006 Elsevier B.V. All rights reserved.