Expression of human apolipoprotein E3 or E4 in the brains of Apoe-/- mice: isoform-specific effects on neurodegeneration

Apolipoprotein (apo) E isoforms are key determinants of sus-ceptibility to Alzheimer’s disease. The apoE4 isoform is the major known genetic risk factor for this disease and is also associated with poor outcome after acute head trauma or stroke. To test the hypothesis that apoE3, but not apoE4, protects against age-related and excitotoxin-induced neurode-generation, we analyzed apoE knockout (Apoe2/2) mice ex-pressing similar levels of human apoE3 or apoE4 in the brain under control of the neuron-specific enolase promoter. Neuro-nal apoE expression was widespread in the brains of these mice. Kainic acid-challenged wild-type or Apoe2/2 mice had a significant loss of synaptophysin-positive presynaptic terminals and microtubule-associated protein 2-positive neuronal den-drites in the neocortex and hippocampus, and a disruption of neurofilament-positive axons in the hippocampus. Expressio