Fibulin‐1 binds the amino‐terminal head of β‐amyloid precursor protein and modulates its physiological function

Genetic studies have implicated amyloid precursor protein (APP) in the pathogenesis of Alzheimer's disease. While accumulating lines of evidence indicate that APP has various functions in cells, little is known about the proteins that modulate its biological activity. Toward this end, we employed a two‐hybrid system to identify potential interacting factors. We now report that fibulin‐1, which contains repetitive Ca2+‐binding EGF‐like elements, binds to APP at its amino‐terminal growth factor‐like domain, the region that is responsible for its neurotrophic activities. Fibulin‐1 expression in the brain is confined to neurons, and is not expressed significantly by astrocytes or microglia. Direct binding of fibulin‐1 to the secreted form of APP (sAPP) was demonstrated with a pull‐down assay using fragments of both fibulin‐1 fused with glutathione‐S transferase and sAPP, produced in bacteria and yeast, respectively. The fibulin‐1/sAPP heteromer was shown to form in the conditioned medium of transfected COS‐7 cells. Furthermore, fibulin‐1 blocks sAPP‐mediated proliferation of primary cultured rat neural stem cells. These results suggest that fibulin‐1 may play a significant role in modulating the neurotrophic activities of APP.

[1]  G. Dawson,et al.  β-amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity , 1995, Cell.

[2]  D. Small,et al.  A heparin-binding domain in the amyloid protein precursor of Alzheimer's disease is involved in the regulation of neurite outgrowth , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[3]  M. Mattson,et al.  Isoform‐Specific Modulation by Apolipoprotein E of the Activities of Secreted β‐Amyloid Precursor Protein , 1997, Journal of neurochemistry.

[4]  M. Mattson,et al.  Secreted Forms of β‐Amyloid Precursor Protein Protect Against Ischemic Brain Injury , 1994 .

[5]  R. J. Fleming,et al.  Specific EGF repeats of Notch mediate interactions with Delta and serrate: Implications for notch as a multifunctional receptor , 1991, Cell.

[6]  D. Selkoe,et al.  Amino-terminal region of the β-amyloid precursor protein activates mitogen-activated protein kinase , 1995, Neuroscience Letters.

[7]  M. Katsuki,et al.  De novo production of alpha 2-macroglobulin in cultured astroglia from rat brain. , 1992, Brain research. Molecular brain research.

[8]  W. Argraves,et al.  The Self-association and Fibronectin-binding Sites of Fibulin-1 Map to Calcium-binding Epidermal Growth Factor-like Domains* , 1997, The Journal of Biological Chemistry.

[9]  R. Timpl,et al.  Sequence of extracellular mouse protein BM-90/fibulin and its calcium-dependent binding to other basement-membrane ligands. , 1993, European journal of biochemistry.

[10]  S. Koizumi,et al.  The effect of a secreted form of β‐amyloid‐precursor protein on intracellular Ca2+ increase in rat cultured hippocampal neurones , 1998, British journal of pharmacology.

[11]  C. Masters,et al.  Crystal structure of the N-terminal, growth factor-like domain of Alzheimer amyloid precursor protein , 1999, Nature Structural Biology.

[12]  D. Selkoe,et al.  Normal and abnormal biology of the beta-amyloid precursor protein. , 1994, Annual review of neuroscience.

[13]  D. Keene,et al.  The association of human fibulin-1 with elastic fibers: an immunohistological, ultrastructural, and RNA study. , 1995, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[14]  Yasuko Nakamura,et al.  Novel Domain-Specific Actions of Amyloid Precursor Protein on Developing Synapses , 1998, The Journal of Neuroscience.

[15]  L. Mucke,et al.  Synaptotrophic effects of human amyloid β protein precursors in the cortex of transgenic mice , 1994, Brain Research.

[16]  J. Kondo,et al.  Neuronal Survival Factor from Bovine Brain Is Identical to Neuron‐Specific Enolase , 1991, Journal of neurochemistry.

[17]  S. Barger,et al.  Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E , 1997, Nature.

[18]  S. Kohsaka,et al.  Plasminogen binds specifically to alpha-enolase on rat neuronal plasma membrane. , 1994, Journal of neurochemistry.

[19]  K. White,et al.  A Drosophila gene encoding a protein resembling the human beta-amyloid protein precursor. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[20]  INTERNATIONAL SOCIETY FOR NEUROCHEMISTRY , 1976 .

[21]  H. Ninomiya,et al.  Amino Acid Sequence Rerms Represents the Active Domain of Amyloid /a4 Protein Precursor That Promotes Fibroblast Growth , 1993 .

[22]  D. Strickland,et al.  Fibulin binds to itself and to the carboxyl-terminal heparin-binding region of fibronectin. , 1992, Journal of Biological Chemistry.

[23]  A. Prochiantz,et al.  The Amyloid Precursor Protein Interacts with Go Heterotrimeric Protein within a Cell Compartment Specialized in Signal Transduction , 1999, The Journal of Neuroscience.

[24]  S. Kohsaka,et al.  The amino-terminal region of amyloid precursor protein is responsible for neurite outgrowth in rat neocortical explant culture. , 1997, Biochemical and biophysical research communications.

[25]  M. Somerman,et al.  Fibulin is an extracellular matrix and plasma glycoprotein with repeated domain structure , 1990, The Journal of cell biology.

[26]  S. Kohsaka,et al.  Involvement of amyloid precursor protein in functional synapse formation in cultured hippocampal neurons , 1998, Journal of neuroscience research.

[27]  S. Takeda,et al.  Ligand-dependent G Protein Coupling Function of Amyloid Transmembrane Precursor (*) , 1995, The Journal of Biological Chemistry.

[28]  C. Y. Chen,et al.  From differentiation to proliferation: the secretory amyloid precursor protein as a local mediator of growth in thyroid epithelial cells. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[29]  E. Appella,et al.  The receptor-binding sequence of urokinase. A biological function for the growth-factor module of proteases. , 1987, The Journal of biological chemistry.

[30]  S. Nagata,et al.  pEF-BOS, a powerful mammalian expression vector. , 1990, Nucleic acids research.

[31]  Y. Imai,et al.  Expression, purification, and neurotrophic activity of amyloid precursor protein-secreted forms produced by yeast. , 1995, Biochemical and biophysical research communications.

[32]  S. Kohsaka,et al.  Amino‐terminal region of secreted form of amyloid precursor protein stimulates proliferation of neural stem cells , 1999, The European journal of neuroscience.

[33]  F. Ruddle,et al.  Embryonic expression pattern of amyloid protein precursor suggests a role in differentiation of specific subsets of neurons. , 1994, The Journal of experimental zoology.

[34]  M. Katsuki,et al.  De novo production of α2-macroglobulin in cultured astroglia from rat brain , 1992 .

[35]  B He,et al.  The C-terminal domain of the regulatory protein NOVH is sufficient to promote interaction with fibulin 1C: a clue for a role of NOVH in cell-adhesion signaling. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[36]  C. Haudenschild,et al.  The Interaction of Fibulin-1 with Fibrinogen , 1995, The Journal of Biological Chemistry.

[37]  M. Mattei,et al.  Human fibulin-1D: molecular cloning, expression and similarity with S1-5 protein, a new member of the fibulin gene family. , 1997, Matrix biology : journal of the International Society for Matrix Biology.

[38]  M. Greenberg,et al.  Distinct roles for bFGF and NT-3 in the regulation of cortical neurogenesis , 1995, Neuron.

[39]  S. Fields,et al.  Analyzing protein-protein interactions using two-hybrid system. , 1995, Methods in enzymology.

[40]  Kanefusa Kato,et al.  Plasminogen Binds Specifically to α‐Enolase on Rat Neuronal Plasma Membrane , 1994 .

[41]  R. Timpl,et al.  A single EGF‐like motif of laminin is responsible for high affinity nidogen binding. , 1993, The EMBO journal.

[42]  M. Mattson,et al.  Secreted forms of beta-amyloid precursor protein protect against ischemic brain injury. , 1994, Journal of neurochemistry.

[43]  I. Mook‐Jung,et al.  Is understanding the biological function of APP important in understanding Alzheimer's disease? , 1999, Journal of Alzheimer's disease : JAD.

[44]  E. Masliah,et al.  Increase of synaptic density and memory retention by a peptide representing the trophic domain of the amyloid beta/A4 protein precursor. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[45]  M. Mattson,et al.  Increased Activity‐Regulating and Neuroprotective Efficacy of α‐Secretase‐Derived Secreted Amyloid Precursor Protein Conferred by a C‐Terminal Heparin‐Binding Domain , 1996, Journal of neurochemistry.

[46]  R. Timpl,et al.  Characterization of a novel calcium-binding 90-kDa glycoprotein (BM-90) shared by basement membranes and serum. , 1990, European journal of biochemistry.

[47]  D. Price,et al.  Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport. , 1990, Proceedings of the National Academy of Sciences of the United States of America.