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 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.
Buttini
M
M
Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94141-9100, USA.
Orth
M
M
Bellosta
S
S
Akeefe
H
H
Pitas
R E
RE
Wyss-Coray
T
T
Mucke
L
L
Mahley
R W
RW
D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000235:genetics; D000818:Animals; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000032:analysis / Q000134:cerebrospinal fluid / Q000235:genetics*; D001923:Brain Chemistry / Q000235:genetics*; D003712:Dendrites / Q000737:chemistry / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D018690:Excitatory Amino Acid Agonists; D005455:Fluorescent Antibody Technique; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D006801:Humans; D007608:Kainic Acid; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000139:chemically induced / Q000235:genetics*; D009498:Neurotoxins / Q000378:metabolism; D017729:Presynaptic Terminals / Q000737:chemistry / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D016708:Synaptophysin / Q000032:analysis
D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D018690:Excitatory Amino Acid Agonists; D009498:Neurotoxins; D012333:RNA, Messenger; D016708:Synaptophysin; D007608:Kainic Acid