Apolipoprotein E associates with beta amyloid peptide of Alzheimer's disease to form novel monofibrils. Isoform apoE4 associates more efficiently than apoE3.

Late-onset and sporadic Alzheimer's disease are associated with the apolipoprotein E (apoE) type 4 allele expressing the protein isoform apoE4. Apolipoprotein E binds avidly to beta amyloid (A beta) peptide, a major component of senile plaque of Alzheimer's disease, in an isoform-specific manner. The apoE4 isoform binds to A beta peptide more rapidly than apoE3. We observed that soluble SDS-stable complexes of apoE3 or apoE4, formed by coincubation with A beta peptide, precipitated after several days of incubation at 37 degrees C with apoE4 complexes precipitating more rapidly than apoE3 complexes. A beta(1-28) and A beta(1-40) peptides were incubated in the presence or absence of apoE3, apoE4, or bovine serum albumin for 4 d at 37 degrees C (pH 7.3). Negative stain electron microscopy revealed that the A beta peptide alone self-assembled into twisted ribbons containing two or three strands but occasionally into multistranded sheets. The apoE/A beta coincubates yielded monofibrils 7 nm in diameter. ApoE4/A beta coincubates yielded a denser matrix of monofibrils than apoE3/A beta coincubates. Unlike purely monofibrillar apoE4/A beta coincubates, apoE3/A beta coincubates also contained double- and triple-stranded structures. Both apoE isoforms were shown by immunogold labeling to be uniformly distributed along the A beta peptide monofibrils. Monofibrils appeared earlier in apoE4/A beta than in apoE3/A beta in time-course experiments. Thus apoE3 and apoE4 each interact with beta amyloid peptide to form novel monofibrillar structures, apoE4 more avidly, a finding consistent with the biochemical and genetic association between apoE4 and Alzheimer's disease.

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

[2]  M. Pericak-Vance,et al.  Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[3]  A. D. Roses,et al.  Association of apolipoprotein E allele €4 with late-onset familial and sporadic Alzheimer’s disease , 2006 .

[4]  T. Wisniewski,et al.  The cerebrospinal-fluid soluble form of Alzheimer's amyloid beta is complexed to SP-40,40 (apolipoprotein J), an inhibitor of the complement membrane-attack complex. , 1993, The Biochemical journal.

[5]  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.

[6]  S D Chen,et al.  [Amyloid precursor protein and Alzheimer's disease]. , 1993, Sheng li ke xue jin zhan [Progress in physiology].

[7]  G. Handelmann,et al.  Effects of apolipoprotein E, beta-very low density lipoproteins, and cholesterol on the extension of neurites by rabbit dorsal root ganglion neurons in vitro. , 1992, Journal of lipid research.

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

[9]  D. Selkoe.  The molecular pathology of Alzheimer's disease , 1991, Neuron.

[10]  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.

[11]  E. Shooter,et al.  A role for apolipoprotein E, apolipoprotein A-I, and low density lipoprotein receptors in cholesterol transport during regeneration and remyelination of the rat sciatic nerve. , 1989, The Journal of clinical investigation.

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

[13]  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.

[14]  D. Selkoe,et al.  Synthetic peptide homologous to beta protein from Alzheimer disease forms amyloid-like fibrils in vitro. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[15]  B. Frangione,et al.  Ten to fourteen residue peptides of Alzheimer's disease protein are sufficient for amyloid fibril formation and its characteristic x-ray diffraction pattern. , 1987, Biochemical and biophysical research communications.

[16]  R. Mahley,et al.  Lipoprotein uptake by neuronal growth cones in vitro. , 1987, Science.

[17]  R. Mahley,et al.  Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins. , 1987, Biochimica et biophysica acta.

[18]  J. Ghiso,et al.  In vitro formation of amyloid fibrils from two synthetic peptides of different lengths homologous to Alzheimer's disease β-protein , 1986 .

[19]  J. Freeman,et al.  Nerve injury stimulates the secretion of apolipoprotein E by nonneuronal cells. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[20]  E. Shooter,et al.  Expression of apolipoprotein E during nerve degeneration and regeneration. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[21]  R. Mahley,et al.  Isolation and characterization of apolipoprotein E. , 1986, Methods in enzymology.

[22]  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.