Behavioral phenotyping of GFAP-apoE3 and -apoE4 transgenic mice: apoE4 mice show profound working memory impairments in the absence of Alzheimer's-like neuropathology

Exp Neurol. 2001 Aug;170(2):326-44. doi: 10.1006/exnr.2001.7715.


For the purpose of studying the potential neurobehavioral effects of different human apolipoprotein E (apoE) isoforms produced within the brain, transgenic (TG) mice were generated in which human apoE3 or apoE4 isoforms were under control of an astrocyte-specific, glial fibrillary acidic protein promoter and these TG mice were bred back to apoE knockout (KO) mice. Behavioral phenotypes of apoE3 and apoE4 TG mice were derived by conducting a longitudinal study in which apoE3 and apoE4 TG mice were compared with apoE KO and wild-type (WT) mice (all male) on several behavioral measures. Analysis of locomotor activity, "open-field" behaviors, acoustic startle/prepulse inhibition, and elevated plus maze data suggested that the apoE TG/KO groups were more "emotionally reactive" than WT mice, with apoE4 mice typically being the most reactive. The absence of performance differences among groups on the rotating holeboard and water navigation tasks suggested intact reference memory processing in apoE TG/KO mice. However, apoE4 mice were profoundly 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/memory results. Western blot analysis revealed no alterations in the level of synaptic, neuronal, or glial markers in neocortex or hippocampus and histologic analysis revealed no evidence of Abeta 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 absence of typical Alzheimer's-like neuropathology.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acoustic Stimulation
  • Aging
  • Alzheimer Disease / pathology
  • Analysis of Variance
  • Animals
  • Apolipoprotein E3
  • Apolipoprotein E4
  • Apolipoproteins E / genetics*
  • Apolipoproteins E / physiology
  • Cues
  • Emotions
  • Escape Reaction / physiology
  • Glial Fibrillary Acidic Protein / genetics*
  • Glial Fibrillary Acidic Protein / physiology
  • Humans
  • Learning / physiology
  • Male
  • Memory Disorders / genetics*
  • Memory Disorders / physiopathology
  • Memory Disorders / psychology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Motor Activity / physiology
  • Phenotype
  • Promoter Regions, Genetic
  • Reaction Time
  • Reflex, Startle
  • Space Perception / physiology
  • Time Factors


  • Apolipoprotein E3
  • Apolipoprotein E4
  • Apolipoproteins E
  • Glial Fibrillary Acidic Protein