Apolipoprotein E Isoform-Specific Differences in Outcome from Focal Ischemia in Transgenic Mice

Apolipoprotein E (apoE), a 34-kD glycosylated lipid-binding protein, is expressed as three common isoforms in humans (E2, E3, or E4). Clinical evidence suggests that the apoE genotype (APOE) may be a risk factor for poor outcome after acute central nervous system injury. This was examined further in transgenic mice constructed with the human APOE3 or APOE4 gene under the control of human promoter and tissue expression elements. Presence of human apoE3 and apoE4 proteins in brains of human APOE homozygous transgenic mice was confirmed by Western blotting. APOE3 (n = 12) and APOE4 (n = 10) mice underwent 60 minutes of middle cerebral artery occlusion. After 24-hour recovery, infarct size was measured. Infarct volumes (mean ± standard deviation) were smaller in the APOE3 group (cortex: APOE3 = 18 ± 4 mm3; APOE4 = 30 ± 11 mm3, P = 0.04; subcortex: APOE3 = 12 ± 4 mm3; APOE4 = 18 ± 4 mm3, P = 0.003). Hemiparesis was less severe in APOE3 mice (P = 0.02). These data indicate that human isoform-specific effects of apoE are relevant to acute pathomechanisms of focal ischemic brain damage when examined in the mouse. APOE transgenic mice may provide an appropriate model to examine the mechanistic basis for the differential effects of human apoE isoforms in acute central nervous system injury.

[1]  D. Laskowitz,et al.  Endogenous apolipoprotein E suppresses LPS‐stimulated microglial nitric oxide production , 1998, Neuroreport.

[2]  W. Strittmatter,et al.  Apolipoprotein E Binds to and Potentiates the Biological Activity of Ciliary Neurotrophic Factor , 1997, The Journal of Neuroscience.

[3]  A. Roses,et al.  Apolipoprotein E-Deficient Mice Have Increased Susceptibility To Focal Cerebral Ischemia , 1997, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[4]  D. Laskowitz,et al.  Apolipoprotein E suppresses glial cell secretion of TNFα , 1997, Journal of Neuroimmunology.

[5]  O. Steward,et al.  Genetic determinants of susceptibility to excitotoxic cell death: implications for gene targeting approaches. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[6]  A. Hofman,et al.  Apolipoprotein E epsilon4 and the risk of dementia with stroke. A population-based investigation. , 1997, JAMA.

[7]  Jonathan D. Smith,et al.  Apolipoprotein E allele–specific antioxidant activity and effects on cytotoxicity by oxidative insults and β–amyloid peptides , 1996, Nature Genetics.

[8]  K. Horsburgh,et al.  Selective alterations in the cellular distribution of apolipoprotein E immunoreactivity following transient cerebral ischaemia in the rat , 1996, Neuropathology and applied neurobiology.

[9]  K. Manton,et al.  Apolipoprotein E polymorphism and stroke in a population sample aged 75 years or more. , 1996, Stroke.

[10]  J. Gilbert,et al.  Human Apolipoprotein E2, E3, and E4 Isoform-Specific Transgenic Mice: Human-like Pattern of GlialandNeuronal Immunoreactivity in Central Nervous System Not Observed in Wild-Type Mice , 1996, Neurobiology of Disease.

[11]  E. Hall,et al.  Induction of apolipoprotein E mRNA in the hippocampus of the gerbil after transient global ischemia. , 1996, Brain research. Molecular brain research.

[12]  A. Roses,et al.  Neurodegeneration in the Central Nervous System of apoE-Deficient Mice , 1995, Experimental Neurology.

[13]  W. Strittmatter,et al.  Interaction of Apolipoprotein E with Laminin Increases Neuronal Adhesion and Alters Neurite Morphology , 1995, Experimental Neurology.

[14]  R. Mahley,et al.  Stable Expression and Secretion of Apolipoproteins E3 and E4 in Mouse Neuroblastoma Cells Produces Differential Effects on Neurite Outgrowth (*) , 1995, The Journal of Biological Chemistry.

[15]  D. Holtzman,et al.  Low density lipoprotein receptor-related protein mediates apolipoprotein E-dependent neurite outgrowth in a central nervous system-derived neuronal cell line. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[16]  E. Hall,et al.  Increased Amyloid Protein Precursor and Apolipoprotein E Immunoreactivity in the Selectively Vulnerable Hippocampus Following Transient Forebrain Ischemia in Gerbils , 1995, Experimental Neurology.

[17]  W. Strittmatter,et al.  ApoE genotype and survival from intracerebral haemorrhage , 1995, The Lancet.

[18]  A. Roses,et al.  Head injury, amyloid β and Alzheimer's disease , 1995, Nature Medicine.

[19]  W. White,et al.  Predictors of cognitive decline after cardiac operation. , 1995, The Annals of thoracic surgery.

[20]  H. Wiśniewski,et al.  Complete cerebral ischemia with short-term survival in rat induced by cardiac arrest. II. Extracellular and intracellular accumulation of apolipoproteins E and J in the brain , 1995, Brain Research.

[21]  B. Tycko,et al.  Synergistic Effects of Traumatic Head Injury and Apolipoprotein-epsilon4 in Patients With Alzheimer's Disease , 1995, Neurology.

[22]  D. Graham,et al.  Apolipoprotein E ε4 allele is associated with deposition of amyloid β-protein following head injury , 1995, Nature Medicine.

[23]  M. Moskowitz,et al.  Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. , 1994, Science.

[24]  A. Roses,et al.  Apolipoprotein E Is Localized to the Cytoplasm of Human Cortical Neurons: A Light and Electron Microscopic Study , 1994, Journal of neuropathology and experimental neurology.

[25]  Guo-Yuan Yang,et al.  Reperfusion‐Induced Injury to the Blood‐Brain Barrier After Middle Cerebral Artery Occlusion in Rats , 1994, Stroke.

[26]  M. Pericak-Vance,et al.  Apolipoprotein E Is Present in Hippocampal Neurons without Neurofibrillary Tangles in Alzheimer's Disease and in Age-Matched Controls , 1994, Experimental Neurology.

[27]  T. Hayek,et al.  Increased plasma and lipoprotein lipid peroxidation in apo E-deficient mice. , 1994, Biochemical and biophysical research communications.

[28]  R. Mahley,et al.  Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro. , 1994, Science.

[29]  V. Ord,et al.  ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis. Demonstration of oxidation-specific epitopes in lesions and high titers of autoantibodies to malondialdehyde-lysine in serum. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[30]  J. Haines,et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. , 1993, Science.

[31]  D. J. Knudsen,et al.  Mouse Strain Differences in Susceptibility to Cerebral Ischemia are Related to Cerebral Vascular Anatomy , 1993, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[32]  M. Pericak-Vance,et al.  Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[33]  E. Rubin,et al.  Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells , 1992, Cell.

[34]  N. Maeda,et al.  Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. , 1992, Science.

[35]  C. Finch,et al.  Astrocytic apolipoprotein E mRNA and GFAP mRNA in hippocampus after entorhinal cortex lesioning. , 1991, Brain research. Molecular brain research.

[36]  G. Stoll,et al.  Macrophages in the peripheral nervous system and astroglia in the central nervous system of rat commonly express apolipoprotein E during development but differ in their response to injury , 1986, Neuroscience Letters.

[37]  L. Curtiss,et al.  Apolipoprotein E is a biologically active constituent of the normal immunoregulatory lipoprotein, LDL-In. , 1986, Journal of immunology.

[38]  K. Reue,et al.  Evolution of apolipoprotein E: mouse sequence and evidence for an 11-nucleotide ancestral unit. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[39]  J. Taylor,et al.  Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system. , 1985, The Journal of clinical investigation.

[40]  E. Shooter,et al.  Denervated sheath cells secrete a new protein after nerve injury. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[41]  T. Edgington,et al.  Regulatory serum lipoproteins: regulation of lymphocyte stimulation by a species of low density lipoprotein. , 1976, Journal of immunology.

[42]  D. Graham,et al.  Apolipoprotein E epsilon 4 allele is associated with deposition of amyloid beta-protein following head injury. , 1995, Nature medicine.

[43]  A. Saunders,et al.  Head injury, amyloid beta and Alzheimer's disease. , 1995, Nature medicine.

[44]  N. Maeda,et al.  Atherosclerosis in mice lacking apo E. Evaluation of lesional development and progression. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[45]  M A Pericak-Vance,et al.  Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. , 1993, Neurology.

[46]  B. Trapp,et al.  Oligodendrocytes but not astrocytes express apolipoprotein E after injury of rat optic nerve , 1989, Glia.

[47]  P. Weinstein,et al.  Reversible middle cerebral artery occlusion without craniectomy in rats. , 1989, Stroke.