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(Stroke. 2002;33:1905.)
© 2002 American Heart Association, Inc.

Original Contributions

Expression of Human Apolipoprotein E Downregulates Amyloid Precursor Protein–Induced Ischemic Susceptibility

Milla Koistinaho, PhD; Mikko I. Kettunen, MSc; David M. Holtzman, MD; Risto A. Kauppinen, MD, PhD; Linda S. Higgins, PhD Jari Koistinaho, MD, PhD

From the A.I. Virtanen Institute for Molecular Sciences (M.K., M.I.K., R.A.K., J.K.), University of Kuopio, the Department of Clinical Pathology (J.K.), Kuopio University Hospital, and the National Bio-NMR Facility (M.I.K., R.A.K.), Kuopio, Finland; the Department of Neurology and Center for the Study of Nervous System Injury (D.M.H.), Washington University School of Medicine, St. Louis, Mo; and Scios Inc (L.S.H.), Sunnyvale, Calif.

Reprint requests to Jari Koistinaho, MD, PhD, A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, PO Box 1627, 70211 Kuopio, Finland. E-mail jari.koistinaho{at}uku.fi

Background and Purpose— 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.

Key Words: amyloid precursor protein • apolipoproteins • cerebral blood flow • ischemia

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