Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer's disease model

The ε4 allele of apolipoprotein E (ApoE) is an important genetic risk factor for Alzheimer's disease (AD). Increasing evidence suggests that this association may be linked to the ability of ApoE to interact with the amyloid‐β (Aβ) peptide and influence its concentration and structure. To determine the effect of ApoE on Aβ and other AD pathology in vivo, we used APPsw transgenic mice and ApoE knockout (−/−) mice to generate APPsw animals that carried two (ApoE +/+), one (ApoE +/−), or no copies (ApoE −/−) of the normal mouse ApoE gene. At 12 months of age, Aβ deposition was present in the cortex and hippocampus and was also prominent within leptomeningeal and cortical blood vessels of all APPsw ApoE +/+ mice. Importantly, although Aβ deposition still occurred in APPsw ApoE −/− mice, no fibrillar Aβ deposits were detected in the brain parenchyma or cerebrovasculature. There was also no neuritic degeneration associated with Aβ deposition in the absence of ApoE. These data demonstrate that ApoE facilitates the formation of both neuritic and cerebrovascular plaques, which are pathological hallmarks of AD and cerebral amyloid angiopathy. Ann Neurol 2000;47:739–747

[1]  R. E. Pitas,et al.  Lipoproteins and their receptors in the central nervous system. Characterization of the lipoproteins in cerebrospinal fluid and identification of apolipoprotein B,E(LDL) receptors in the brain. , 1987, The Journal of biological chemistry.

[2]  A. Fagan,et al.  Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[3]  B. Ghetti,et al.  A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. , 1991, Science.

[4]  B. Sommer,et al.  Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[5]  A. M. Saunders,et al.  Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease , 1994, Nature Genetics.

[6]  S. Younkin,et al.  Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice , 1996, Science.

[7]  D. Borchelt,et al.  Genetic modification of the phenotypes produced by amyloid precursor protein overexpression in transgenic mice. , 1997, Human molecular genetics.

[8]  M. Lalowski,et al.  Is Alzheimer's disease an apolipoprotein E amyloidosis? , 1995, The Lancet.

[9]  J. D. Olmos,et al.  A modified cupric-silver technique for the impregnation of degenrating neurons and their processes , 1981, Brain Research.

[10]  J. Olney,et al.  MK-801 neurotoxicity in male mice: histologic effects and chronic impairment in spatial learning , 1996, Brain Research.

[11]  B. Hyman,et al.  Apolipoprotein E ϵ4 and cerebral hemorrhage associated with amyloid angiopathy , 1995 .

[12]  M. A. Neumann.  COMBINED AMYLOID VASCULAR CHANGES AND ARGYROPHILIC PLAQUES IN THE CENTRAL NERVOUS SYSTEM , 1960, Journal of neuropathology and experimental neurology.

[13]  Mark J. West,et al.  New stereological methods for counting neurons , 1993, Neurobiology of Aging.

[14]  Thomas Wisniewski,et al.  Apolipoprotein E: A pathological chaperone protein in patients with cerebral and systemic amyloid , 1992, Neuroscience Letters.

[15]  H. Brewer,et al.  Amyloid-associated proteins α1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer β-protein into filaments , 1994, Nature.

[16]  A. Fagan,et al.  Glial Fibrillary Acidic Protein–Apolipoprotein E (apoE) Transgenic Mice: Astrocyte-Specific Expression and Differing Biological Effects of Astrocyte-Secreted apoE3 and apoE4 Lipoproteins , 1998, The Journal of Neuroscience.

[17]  R. Wetzel,et al.  Seeding of A beta fibril formation is inhibited by all three isotypes of apolipoprotein E. , 1996, Biochemistry.

[18]  Bradley T. Hyman,et al.  Apolipoprotein E ε4 Is Associated With the Presence and Earlier Onset of Hemorrhage in Cerebral Amyloid Angiopathy , 1996 .

[19]  D. Graham,et al.  High frequency of apolipoprotein E ϵ2 Allele in hemorrhage due to cerebral amyloid angiopathy , 1997, Annals of neurology.

[20]  R N Kalaria,et al.  Apolipoprotein E-epsilon4 alleles in cerebral amyloid angiopathy and cerebrovascular pathology associated with Alzheimer's disease. , 1996, The American journal of pathology.

[21]  L. Thal,et al.  The apolipoprotein E epsilon 4 allele is associated with increased neuritic plaques and cerebral amyloid angiopathy in Alzheimer's disease and Lewy body variant , 1996, Neurology.

[22]  E. Otomo,et al.  Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease and kuru plaque amyloid in Creutzfeldt-Jakob disease , 1991, Brain Research.

[23]  B. Hyman,et al.  APPSW Transgenic Mice Develop Age‐related Aβ Deposits and Neuropil Abnormalities, but no Neuronal Loss in CA1 , 1997, Journal of neuropathology and experimental neurology.

[24]  J. Poirier,et al.  Apolipoprotein E isoform-specific reduction of extracellular amyloid in neuronal cultures. , 1999, Brain research. Molecular brain research.

[25]  H. Vinters.  Cerebral amyloid angiopathy. A critical review. , 1987, Stroke.

[26]  S. Paul,et al.  Lack of apolipoprotein E dramatically reduces amyloid β-peptide deposition , 1997, Nature Genetics.

[27]  B. Tycko,et al.  The apolipoprotein ε4 allele in patients with Alzheimer's disease , 1993, Annals of neurology.

[28]  A. Fagan,et al.  Expression of human apolipoprotein E reduces amyloid-beta deposition in a mouse model of Alzheimer's disease. , 1999, The Journal of clinical investigation.

[29]  D. Holtzman,et al.  Nascent Astrocyte Particles Differ from Lipoproteins in CSF , 1998, Journal of neurochemistry.

[30]  L. Mucke,et al.  Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein , 1995, Nature.

[31]  Plaque-induced neurite abnormalities: implications for disruption of neural networks in Alzheimer's disease. , 1999 .

[32]  J. Hardy,et al.  Amyloid precursor protein mutation causes Alzheimer's disease in a Swedish family , 1994, Neuroscience Letters.

[33]  B. Hyman,et al.  Microglial response to amyloid plaques in APPsw transgenic mice. , 1998, The American journal of pathology.

[34]  A. Roses,et al.  Apolipoprotein E associates with beta amyloid peptide of Alzheimer's disease to form novel monofibrils. Isoform apoE4 associates more efficiently than apoE3. , 1994, The Journal of clinical investigation.

[35]  M. Tabaton,et al.  Opposite roles of apolipoprotein E in normal brains and in Alzheimer's disease. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[36]  B. Hyman,et al.  Aβ Deposition Is Associated with Neuropil Changes, but not with Overt Neuronal Loss in the Human Amyloid Precursor Protein V717F (PDAPP) Transgenic Mouse , 1997, The Journal of Neuroscience.

[37]  P. Lansbury,et al.  Apolipoprotein E is a kinetic but not a thermodynamic inhibitor of amyloid formation: implications for the pathogenesis and treatment of Alzheimer disease. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[38]  R. Mahley,et al.  Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. , 1988, Science.

[39]  D. Borchelt,et al.  Age-related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins , 1995, Neuron.

[40]  R. Martins,et al.  Apolipoprotein E promotes the binding and uptake of β-amyloid into Chinese hamster ovary cells in an isoform-specific manner , 1999, Neuroscience.

[41]  J. Growdon,et al.  Structure and Functions of Human Cerebrospinal Fluid Lipoproteins from Individuals of Different APOE Genotypes , 1998, Experimental Neurology.

[42]  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.

[43]  M. Mesulam,et al.  β-Amyloid and the pathogenesis of alzheimer's disease , 1991 .

[44]  R. Motter,et al.  Amyloid precursor protein processing and Aβ42 deposition in a transgenic mouse model of Alzheimer disease , 1997 .

[45]  B. Permanne,et al.  Detection of apolipoprotein E/dimeric soluble amyloid beta complexes in Alzheimer's disease brain supernatants. , 1997, Biochemical and biophysical research communications.

[46]  G. Glenner,et al.  Differences Between Vascular and Plaque Core Amyloid in Alzheimer's Disease , 1988, Journal of neurochemistry.

[47]  A D Roses,et al.  Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[48]  S. Paul,et al.  Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer's disease. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[49]  C. Wernstedt,et al.  Characterization of stable complexes involving apolipoprotein E and the amyloid β peptide in Alzheimer's disease brain , 1995, Neuron.

[50]  S. Greenberg,et al.  Association of apolipoprotein E ϵ2 and vasculopathy in cerebral amyloid angiopathy , 1998, Neurology.

[51]  J. Breslow,et al.  Apolipoprotein E and the apolipoprotein E-deficient mouse. , 1995, Annual review of nutrition.

[52]  T. Wisniewski,et al.  Fibrillogenesis in Alzheimer's disease of amyloid beta peptides and apolipoprotein E. , 1995, The Biochemical journal.

[53]  D. Selkoe,et al.  Protein chemical and immunocytochemical studies of meningovascular β-amyloid protein in Alzheimer's disease and normal aging , 1988, Brain Research.

[54]  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.

[55]  Khadija Iqbal,et al.  Peptide compositions of the cerebrovascular and senile plaque core amyloid deposits of Alzheimer's disease. , 1993, Archives of biochemistry and biophysics.

[56]  M J Ball,et al.  beta-Amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.