Behavioral phenotyping of GFAP-ApoE3 and-ApoE4 transgenic mice: ApoE4 miceshow profound working memory impairments in the absence of Alzheimer's-like neuropathology

For the purpose of studying the potential neurobehavioral effects of differ ent human apolipoprotein E (apoE) isoforms produced within the brain, trans genic (TG) mice were generated in which human apoE3 or apoE4 isoforms were under control of an astrocyte-specific, glial fibrillary acidic protein pro moter and these TG mice were bred back to apoE knockout (KO) mice. Behavior al phenotypes of apoE3 and apoE4 TG mice were derived by conducting a longi tudinal study in which apoE3 and apoE4 TG mice were compared with apoE KO a nd wild-type (WT) mice (all male) on several behavioral measures. Analysis of locomotor activity, "open-field" behaviors, acoustic startle/prepulse in hibition, and elevated plus maze data suggested that the apoE TG/KO groups were more "emotionally reactive" than WT mice, with apoE4 mice typically be ing the most reactive. The absence of performance differences among groups on the rotating holeboard and water navigation tasks suggested intact refer ence memory processing in apoE TG/KO mice. However, apoE4 mice were profoun dly impaired on a working memory-based protocol in the radial arm maze (11- 14 months). Nonassociative factors (sensorimotor capacities or emotionality differences) did not appear to confound interpretation of the learning/mem ory results. Western blot analysis revealed no alterations in the level of synaptic, neuronal, or glial markers in neocortex or hippocampus and histol ogic analysis revealed no evidence of A beta deposition or neuritic plaques in the apoE KO/TG mice. Our findings suggest that apoE4 expression in the brain may have selective deleterious effects on memory function in the abse nce of typical Alzheimer's-like neuropathology. (C) 2001 Academic Press.