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PMID: 10366621 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 19 ·No. 12 ·1999-06-15 ·Pages 4867-80

Buttini M, Orth M, Bellosta S, Akeefe H, Pitas RE, Wyss-Coray T, Mucke L, Mahley RW

Abstract

Apolipoprotein (apo) E isoforms are key determinants of susceptibility 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 neurodegeneration, we analyzed apoE knockout (Apoe-/-) mice expressing similar levels of human apoE3 or apoE4 in the brain under control of the neuron-specific enolase promoter. Neuronal apoE expression was widespread in the brains of these mice. Kainic acid-challenged wild-type or Apoe-/- mice had a significant loss of synaptophysin-positive presynaptic terminals and microtubule-associated protein 2-positive neuronal dendrites in the neocortex and hippocampus, and a disruption of neurofilament-positive axons in the hippocampus. Expression of apoE3, but not of apoE4, protected against this excitotoxin-induced neuronal damage. ApoE3, but not apoE4, also protected against the age-dependent neurodegeneration seen in Apoe-/- mice. These differences in the effects of apoE isoforms on neuronal integrity may relate to the increased risk of Alzheimer's disease and to the poor outcome after head trauma and stroke associated with apoE4 in humans.

MeSH Terms
Aging/metabolism Alzheimer Disease/cerebrospinal fluid,genetics Animals Apolipoprotein E3 Apolipoprotein E4 Apolipoproteins E/analysis,cerebrospinal fluid,genetics Brain Chemistry/genetics Dendrites/chemistry,metabolism Enzyme-Linked Immunosorbent Assay Excitatory Amino Acid Agonists Fluorescent Antibody Technique Gene Expression Regulation, Developmental Genotype Humans Kainic Acid Mice Mice, Inbred C57BL Mice, Knockout Nerve Degeneration/chemically induced,genetics Neurotoxins/metabolism Presynaptic Terminals/chemistry,metabolism RNA, Messenger/analysis Synaptophysin/analysis
Chemicals
Apolipoprotein E3 Apolipoprotein E4 Apolipoproteins E Excitatory Amino Acid Agonists Neurotoxins RNA, Messenger Synaptophysin Kainic Acid
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Buttini M
Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94141-9100, USA.
Orth M
Bellosta S
Akeefe H
Pitas R E
Wyss-Coray T
Mucke L
Mahley R W
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
Published
1999-06-15
Pages
4867-80
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6782676
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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