Elsevier

Neuroscience

Volume 97, Issue 2, April 2000, Pages 207-210
Neuroscience

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

https://doi.org/10.1016/S0306-4522(00)00069-5Get rights and content

Abstract

Apolipoprotein E fulfills fundamental functions in lipid transport and neural tissue repair after injury.6., 8. Its three most common isoforms (E2, E3, and E4) are critical determinants of diverse human diseases, including major cardiovascular and neurodegenerative disorders.8., 14. Apolipoprotein E4 is associated with an increased risk for Alzheimer’s disease3., 5. and poor clinical outcome after head injury or stroke.11., 16. The precise role of apolipoprotein E4 in these conditions remains unknown. To characterize the effects of human apolipoprotein E isoforms in vivo, we analysed transgenic Apoe knockout mice that express apolipoprotein E3 or E4 or both in the brain. Hemizygous and homozygous apolipoprotein E3 mice were protected against age-related and excitotoxin-induced neurodegeneration, whereas apolipoprotein E4 mice were not. Apolipoprotein E3/E4 bigenic mice were as susceptible to neurodegeneration as apolipoprotein E4 singly-transgenic mice. At eight months of age neurodegeneration was more severe in homozygous than in hemizygous apolipoprotein E4 mice consistent with a dose effect. Thus, apolipoprotein E4 is not only less neuroprotective than apolipoprotein E3 but also acts as a dominant negative factor that interferes with the beneficial function of apolipoprotein E3. The inhibition of this apolipoprotein E4 activity may be critical for the prevention and treatment of neurodegeneration in APOE ε4 carriers.

Section snippets

Animals

All the animal experiments were performed according to institutional guidelines, and every effort was made to minimize animal suffering and to keep the number of animals used to a minimum. The generation of E3/0 and E4/0 mice has been described.2 E3/E4 mice were generated by crossing E3/0 with E4/0 mice. E3/0, E4/0, and 0/0 mice were obtained from the same crosses. Homozygous mice (E3/E3 or E4/E4) were obtained by crossing hemizygous mice of the same genotype. All mice were C57BL/6J and Apoe-/-

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    The increased production of APOE3, but not APOE4, in the hippocampus stimulates the repair of local lesion-induced damage [56]. Moreover, synaptic and dendritic alterations and significant learning deficits, all of which associate with local neurite remodeling, are observed in ApoE-deficient mice [57] and APOE4 transgenic mice [58–63]. Notably, APOE3, but not APOE4, protects against excitotoxin-induced neuronal damage in mice [58].

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