title: Western-type diet modulates inflammatory responses and impairs functional outcome following permanent middle cerebral artery occlusion in aged mice expressing the human apolipoprotein E4 allele.
abstract: BACKGROUND
  Numerous clinical trials in stroke have failed, most probably partially due to preclinical studies using young, healthy male rodents with little relevance to the heterogenic conditions of human stroke. Co-morbid conditions such as atherosclerosis and infections coupled with advanced age are known to contribute to increased risk of cerebrovascular diseases. Clinical and preclinical studies have shown that the E4 allele of human apolipoprotein (ApoE4) is linked to poorer outcome in various conditions of brain injury and neurodegeneration, including cerebral ischemia. Since ApoE is a known regulator of lipid homeostasis, we studied the impact of a high-cholesterol diet in aged mice in the context of relevant human ApoE isoforms on the outcome of focal brain ischemia.
  
  
  METHODS
  Aged mice expressing human E3 and E4 isoforms of ApoE in C57BL/6J background and C57BL/6J mice fed on either a high-fat diet or a normal diet underwent permanent middle cerebral artery occlusion. The impact of a high-cholesterol diet was assessed by measuring the serum cholesterol level and the infarction volume was determined by magnetic resonance imaging. Sensorimotor deficits were assessed using an adhesive removal test and the findings were correlated with inflammatory markers.
  
  
  RESULTS
  We show that expression of human ApoE4 renders aged mice fed with a western-type diet more susceptible to sensorimotor deficits upon stroke. These deficits are not associated with atherosclerosis but are accompanied with altered astroglial activation, neurogenesis, cyclooxygenase-2 immunoreactivity and increased plasma IL-6.
  
  
  CONCLUSIONS
  Our results support the hypothesis that ApoE alleles modify the inflammatory responses in the brain and the periphery, thus contributing to altered functional outcome following stroke.
authors: Department of Neurobiology, A, I, Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, P,O, Box 1627, FI-70211 Kuopio, Finland. jari.koistinaho@uef.fi.
authors: Hiramani
authors: H
authors: Dhungana
authors: Taisia
authors: T
authors: Rolova
authors: Ekaterina
authors: E
authors: Savchenko
authors: Sara
authors: S
authors: Wojciechowski
authors: Kaisa
authors: K
authors: Savolainen
authors: Anna-Kaisa
authors: AK
authors: Ruotsalainen
authors: Patrick M
authors: PM
authors: Sullivan
authors: Jari
authors: J
authors: Koistinaho
authors: Tarja
authors: T
authors: Malm
mesh_terms: D000375:Aging; D000483:Alleles; D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics*; D050197:Atherosclerosis / Q000453:epidemiology; D015897:Comorbidity; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000235:genetics* / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity; D020127:Recovery of Function / Q000235:genetics*
chemical_list: D053327:Apolipoprotein E4
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