title: Cellular source of apolipoprotein E4 determines neuronal susceptibility to excitotoxic injury in transgenic mice.
abstract: The lipid transport protein apolipoprotein E (apoE) is abundantly expressed in the brain. Its main isoforms in humans are apoE2, apoE3, and apoE4. ApoE4 is the major known genetic risk factor for Alzheimer's disease and also contributes to the pathogenesis of various other neurological conditions. In the central nervous system, apoE is synthesized by glial cells and neurons, but it is unclear whether the cellular source affects its biological activities. To address this issue, we induced excitotoxic injury by systemic kainic acid injection in transgenic Apoe knockout mice expressing human apoE isoforms in astrocytes or neurons. Regardless of its cellular source, apoE3 expression protected neuronal synapses and dendrites against the excitotoxicity seen in apoE-deficient mice. Astrocyte-derived apoE4, which has previously been shown to have detrimental effects in vitro, was as excitoprotective as apoE3 in vivo. In contrast, neuronal expression of apoE4 was not protective and resulted in loss of cortical neurons after excitotoxic challenge, indicating that neuronal apoE4 promotes excitotoxic cell death. Thus, an imbalance between astrocytic (excitoprotective) and neuronal (neurotoxic) apoE4 expression may increase susceptibility to diverse neurological diseases involving excitotoxic mechanisms.
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158-2261, USA. manuel.buttini@elan.com
authors.forename: Manuel
authors.initials: M
authors.lastname: Buttini
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Gui-Qiu
authors.initials: GQ
authors.lastname: Yu
authors.forename: Jorge J
authors.initials: JJ
authors.lastname: Palop
authors.forename: Shengjun
authors.initials: S
authors.lastname: Chang
authors.forename: Aubrey
authors.initials: A
authors.lastname: Bernardo
authors.forename: Carol
authors.initials: C
authors.lastname: Lin
authors.forename: Tony
authors.initials: T
authors.lastname: Wyss-Coray
authors.forename: Yadong
authors.initials: Y
authors.lastname: Huang
authors.forename: Lennart
authors.initials: L
authors.lastname: Mucke
mesh_terms: D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006801:Humans; D007608:Kainic Acid / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*
chemical_list: D053327:Apolipoprotein E4; D018690:Excitatory Amino Acid Agonists; D020033:Protein Isoforms; D007608:Kainic Acid