title: Expression of human apolipoprotein E downregulates amyloid precursor protein-induced ischemic susceptibility.
abstract: OBJECTIVE
  Epidemiological findings and experimental data on transgenic mice show that Alzheimer's disease-related changes render the brain more susceptible to ischemic damage. We studied whether the previously observed vulnerability in mice overexpressing the 751-amino-acid isoform of human amyloid precursor protein (APP751) is regulated by human apolipoprotein E (apoE) alleles, which determine the relative risk for Alzheimer's disease and the susceptibility to various forms of acute brain damage.
  
  
  METHODS
  Aged apoE knock out (KO) mice, mice overexpressing APP751 in the apoE KO background and mice expressing either human apoE3 or apoE4 and APP751 in the apoE KO background were exposed to permanent occlusion of the middle cerebral artery (MCA). Infarct volumes were quantified from T2-weighted magnetic resonance images 24 hours after the MCA occlusion. Local cortical blood flow was monitored by laser Doppler flowmetry. Ischemia-induced microgliosis was detected by immunohistochemistry.
  
  
  RESULTS
  Overexpression of human APP751 significantly increased the infarct volumes in apoE KO mice. Furthermore, this APP751-induced ischemic vulnerability was attenuated by the coexpression of either human apoE isoform. MCA occlusion resulted in a similar relative reduction in cortical blood flow in all mouse groups. Vascular anatomy showed no variation in the MCA territory between the groups. Instead, the expression of human apoE isoforms reduced the ischemia-induced microgliosis.
  
  
  CONCLUSIONS
  Expression of either the human apoE3 or apoE4 isoform protects against the increased ischemic vulnerability observed in aged mice overexpressing human APP751, probably by modulating the inflammatory response induced by MCA occlusion.
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland.
authors.forename: Milla
authors.initials: M
authors.lastname: Koistinaho
authors.forename: Mikko I
authors.initials: MI
authors.lastname: Kettunen
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.forename: Risto A
authors.initials: RA
authors.lastname: Kauppinen
authors.forename: Linda S
authors.initials: LS
authors.lastname: Higgins
authors.forename: Jari
authors.initials: J
authors.lastname: Koistinaho
mesh_terms: D000375:Aging / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D000818:Animals; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D001783:Blood Flow Velocity; D002545:Brain Ischemia / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D002540:Cerebral Cortex / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D005911:Gliosis / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000473:pathology; D017078:Laser-Doppler Flowmetry; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology
chemical_list: D016564:Amyloid beta-Protein Precursor; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D020033:Protein Isoforms