No effect of apolipoprotein E on neuronal cell death due to excitotoxic and apoptotic agents in vitro and neonatal hypoxic ischaemia in vivo.
The epsilon4 allele of apolipoprotein E (apoE) is a genetic risk factor for Alzheimer's disease. Studies also suggest that the epsilon4 allele may be a risk factor for poor outcome following head trauma, brain haemorrhage and ischaemia. The mechanism by which the presence of an apoE epsilon4 allele and certain brain injuries act to predispose to Alzheimer's disease and poor outcome following brain injury is unknown. We questioned whether poor outcome after brain injury was due to direct modification by apoE protein and its gene variants of susceptibility to glutamate-mediated excitotoxic injury and apoptosis, mechanisms of cell death which occur following ischaemia and trauma. We investigated the effect of the presence or absence of endogenous murine apoE protein and different apoE isoforms in modification of the survival of murine embryonic cortical neurons exposed to the glutamate agonist, N-methyl-D-aspartic acid (NMDA) or apoptotic insult by staurosporine, and on the amount of brain injury sustained following a hypoxic-ischaemic insult in vivo to the brain of neonatal mice transgenically expressing human apoE epsilon3 or epsilon4. Our data provide evidence that apoE does not appear to alter neuronal viability following diverse types of acute neuronal insult, e.g. hypoxic-ischaemic or acute exposure to injurious agents in the models we have examined. This suggests that if apoE does modify the extent of brain damage and recovery after injury, it seems unlikely to be a result of direct or indirect modulation of excitotoxic or apoptotic cell death.
Lendon
C L
CL
Department of Psychiatry, University of Birmingham, Queen Elizabeth Psychiatric Hospital, UK. c.l.lendon@bham.ac.uk
Han
B H
BH
Salimi
K
K
Fagan
A M
AM
Behrens
M I
MI
Muller
M C
MC
Holtzman
D M
DM
D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology / Q000503:physiopathology*; D066298:In Vitro Techniques; D051379:Mice; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000166:cytology*; D009498:Neurotoxins / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology
D000906:Antibodies; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D009498:Neurotoxins; D016202:N-Methylaspartate; D019311:Staurosporine