Dominant negative effects of apolipoprotein E4 revealed in transgenic models of neurodegenerative disease

Apolipoprotein E fulfills fundamental functions in lipid transport and neur al tissue repair after injury.(6,8) Its three most common isoforms (E2, E3, and E4) are critical determinants of diverse human diseases, including maj or cardiovascular and nenrodegenerative disorders.(8,14) Apolipoprotein E4 is associated with an increased risk for Alzheimer's disease(3,5) and poor clinical outcome after head injury or stroke.(11,16) The precise role of ap olipoprotein E4 in these conditions remains unknown. To characterize the ef fects of human alpolipoprotein E isoforms in vivo, we analysed transgenic A poe knockout mice that express apolipoprotein E3 or E4 or both in the brain . Hemizygous and homozygous apolipoprotein E3 mice were protected against a ge-related and excitotoxin-induced neurodegeneration, whereas apolipoprotei n E4 mice were not. Apolipoprotein E3/E4 bigenic mice were as susceptible t o neurodegeneration as apolipoprotein E4 singly-transgenic mice. At eight m onths of age neurodegeneration was more severe in homozygous than in hemizy gous apolipoprotein E4 mice consistent with a dose effect. Thus, apolipopro tein E4 is not only less neuroprotective than apolipoprotein E3 but also ac ts as a dominant negative factor that interferes with the beneficial functi on of apolipoprotein E3, The inhibition of this apolipoprotein E4 activity may be critical for the prevention and treatment of neurodegeneration in AP OE E4 carriers. (C) 2000 IBRO, Published by Elsevier Science Ltd.