KOTg and the KO mice were considerably debilitated by the age of 9-10 months as previously reported for aB-crystallin/HspB2deficient mice. At this age, WTTg mice do not have significant levels of plaque pathology and plaques develop only in mice older than 10-12 months of age. Immunohistochemical examination of mice brains at 7 months revealed no plaques under our experimental conditions. However, it is thought that plaques may not be causative and others have shown that decreased dendritic spine density, impaired long-term potentiation, and behavioral deficits occurred many months before detectable plaques. We observed a modest locomotor deficit in WTTg mice by open field tests suggesting that the expression of hAPP affected muscle function. In Tg2576 mice, expression of the APP transgene has been observed in muscle tissue where the function of aB-crystallin and HspB2 is expected to be crucial. The presence of amyloid oligomers in muscle cells has been shown to have potent toxicity. Thus, the high degree of synergistic toxic effects of aB-crystallin/HspB2 loss and transgene expression in the skeletal muscle precluded the examination of plaque pathology at later ages. Because sHsps block the fibrillization and toxicity of Ab it is suggested that in the Y-27632 absence of aBcrystallin/HspB2 enhanced Ab toxicity may contribute to the manifestation of the synergistic phenotypes. An alternative explanation for the locomotion defect is that since APP is expressed throughout the brain in this mouse, it might contribute to deficits in the brain motor centers. The locomotion defects observed in the WTTg mice are important because these transgenic mice are routinely used in learning and memory tests that involve locomotion. In agreement with our observations, motor deficits in Tg2576 have been observed at 6–7 months in a recent publication. No significant perturbation in the motor reflexes was observed in WTTg mice as the mice could perceive and respond to thermal stimulus in the supraspinal nociception test. However, reduced chaperone levels in the transgenic mice produced a sensory defect suggesting that this synergism also affected nociception. In the WTTg mice, we also observed a significant limitation in their ability to associate mild aversive stimulus with the environmental context but not with an auditory cue. This difference in associative learning can be interpreted as follows – Contextual learning may be based on weak associations between the footshock and diverse signals and thereby differences between WT and WTTg are manifested significantly. It has been thought that animals may associate only a subset of contextual elements, which leads to weak associative learning. The inability of WTTg to associate and integrate the complex contextual signals with the aversive stimulus indicates a reduced hippocampal function. Contextual associative learning deficit in Tg2576 has been previously observed.