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Apolipoprotein E deficiency worsens outcome from global cerebral ischemia in the mouse
H Sheng1, D T Laskowitz, G B Mackensen
1Departments of Anesthesiology, Duke University Medical Center, Durham, NC, USA.
Background And Purpose:
Apolipoprotein E (apoE) has been found relevant in a variety of central nervous system disorders. This experiment examined the effect of endogenous murine apoE on selective neuronal necrosis resulting from a transient forebrain ischemia insult.
Methods:
ApoE deficient (n=16) and wild type (n=17) halothane-anesthetized mice were subjected to severe forebrain ischemia (10 minutes of bilateral carotid occlusion and systemic hypotension). After 3 days' recovery, brain injury was determined histologically. In other apoE-deficient and wild-type mice, regional cerebral blood flow (CBF) was determined by 14C-iodoantipyrine autoradiography 10 minutes before, 5 minutes after onset of, and 30 minutes after reperfusion from 10 minutes of forebrain ischemia.
Results:
The percentage of dead hippocampal CA1 neurons (mean+/-SD) was greater in the apoE-deficient group (apoE deficient=67+/-30%; wild type=37+/-33%; P=0.011). A similar pattern was observed in the caudoputamen (P=0.002) and neocortex (P=0.014). Cerebral blood flow was similar between groups at each measurement interval. Marked hypoperfusion persisted in both groups at 30 minutes after ischemia.
Conclusions:
ApoE deficiency worsens ischemic outcome. This is not attributable to effects on CBF. A role of apoE in the cerebral response to global ischemia is consistent with prior reports that murine apoE deficiency increases infarct size resulting from focal cerebral ischemia.
Insights
Apolipoprotein E (apoE) deficiency worsens brain damage after ischemic stroke in mice. This effect is not due to changes in cerebral blood flow (CBF).
Area of Science:
- Neuroscience
- Ischemic Stroke Research
- Apolipoprotein E Biology
Background:
- Apolipoprotein E (apoE) plays a role in various central nervous system disorders.
- Understanding apoE's function in brain injury is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the impact of endogenous murine apoE on neuronal death following transient forebrain ischemia.
- To determine if apoE influences the brain's response to global ischemic insults.
Main Methods:
- Forebrain ischemia was induced in apoE-deficient and wild-type mice.
- Histological analysis assessed brain injury, specifically neuronal necrosis in key brain regions.
- Regional cerebral blood flow (CBF) was measured using 14C-iodoantipyrine autoradiography.
Main Results:
- ApoE-deficient mice exhibited significantly higher percentages of dead hippocampal CA1 neurons compared to wild-type mice.
- Increased neuronal death was also observed in the caudoputamen and neocortex of apoE-deficient mice.
- Cerebral blood flow remained comparable between groups, and hypoperfusion persisted post-ischemia.
Conclusions:
- ApoE deficiency exacerbates ischemic brain injury, independent of alterations in cerebral blood flow.
- These findings support a protective role for apoE in the cerebral response to global ischemia.
- The results align with previous studies showing increased infarct size in apoE-deficient mice following focal cerebral ischemia.