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Spatial disorientation is one of the earliest symptoms in Alzheimer’s disease and allocentric deficits can already be detected in the asymptomatic preclinical stages of the disease. The Morris Water Maze (MWM) is used to study spatial learning in rodent models. Here we investigated the spatial memory of female 3, 7 and 12 month-old Alzheimer Tg4-42 mice in comparison to wild-type control animals. Conventional behavior analysis of escape latencies and quadrant preference revealed spatial memory and reference memory deficits in female 7 and 12 month-old Tg4-42 mice. In contrast, conventional analysis of the MWM indicated an intact spatial memory in 3 month-old Tg4-42 mice. However, a detailed analysis of the swimming strategies demonstrated allocentric-specific memory deficits in 3 month-old Tg4-42 mice before the onset of severe memory deficits. Furthermore, we could show that the spatial reference memory deficits in aged Tg4-42 animals are caused by the lack of allocentric and spatial strategies. Analyzing search strategies in the MWM allows to differentiate between hippocampus-dependent allocentric and hippocampus-independent egocentric search strategies. The spatial navigation impairments in young Tg4-42 mice are well in line with the hypometabolism and synaptic deficits in the hippocampus. Therefore, analyzing search strategies in the Tg4-42 model can be a powerful tool for preclinical drug testing and identifying early therapeutic successes.

Search strategy analysis of Tg4-42 Alzheimer Mice in the Morris Water Maze reveals early spatial navigation deficits