An intracellular protein that binds amyloid-β peptide and mediates neurotoxicity in Alzheimer's disease

Amyloid-β is a neurotoxic peptide which is implicated in the pathogenesis of Alzheimer's disease. It binds an intracellular polypeptide known as ERAB, thought to be a hydroxysteroid dehydrogenase enzyme, which is expressed in normal tissues, but is overexpressed in neurons affected in Alzheimer's disease. ERAB immunoprecipitates with amyloid-β, and when cell cultures are exposed to amyloid-β, ERAB inside the cell is rapidly redistributed to the plasma membrane. The toxic effect of amyloid-β on these cells is prevented by blocking ERAB and is enhanced by overexpression of ERAB. By interacting with intracellular amyloid-β, ERAB may therefore contribute to the neuronal dysfunction associated with Alzheimer's disease.

[1]  D. D'urso,et al.  Cerebrovascular smooth muscle cells internalize Alzheimer amyloid beta protein via a lipoprotein pathway: implications for cerebral amyloid angiopathy. , 1997, Laboratory investigation; a journal of technical methods and pathology.

[2]  F. Maxfield,et al.  Microglial Cells Internalize Aggregates of the Alzheimer's Disease Amyloid β-Protein Via a Scavenger Receptor , 1996, Neuron.

[3]  R. Bucala,et al.  Advanced glycation end products contribute to amyloidosis in Alzheimer disease. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[4]  S. Fields,et al.  A novel genetic system to detect protein–protein interactions , 1989, Nature.

[5]  C. Masters,et al.  Intracellular and secreted Alzheimer beta-amyloid species are generated by distinct mechanisms in cultured hippocampal neurons. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[6]  C. Glabe,et al.  Intracellular Aβ1-42 Aggregates Stimulate the Accumulation of Stable, Insoluble Amyloidogenic Fragments of the Amyloid Precursor Protein in Transfected Cells (*) , 1995, The Journal of Biological Chemistry.

[7]  T. Sunderland,et al.  Participation of Presenilin 2 in Apoptosis: Enhanced Basal Activity Conferred by an Alzheimer Mutation , 1996, Science.

[8]  Weiming Xia,et al.  Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice , 1997, Nature Medicine.

[9]  K. Yoshikawa,et al.  Degeneration in vitro of post-mitotic neurons overexpressing the Alzheimer amyloid protein precursor , 1992, Nature.

[10]  T. Iwatsubo,et al.  Amino- and carboxyl-terminal heterogeneity of β-amyloid peptides deposited in human brain , 1996, Neuroscience Letters.

[11]  G. Benzi,et al.  Are reactive oxygen species involved in Alzheimer's disease? , 1995, Neurobiology of Aging.

[12]  M. Kozak.  An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs. , 1987, Nucleic acids research.

[13]  M. Schembri,et al.  Phosphate concentration regulates transcription of the Acinetobacter polyhydroxyalkanoic acid biosynthetic genes , 1995, Journal of bacteriology.

[14]  D. Ghosh,et al.  Three-dimensional structure of holo 3 alpha,20 beta-hydroxysteroid dehydrogenase: a member of a short-chain dehydrogenase family. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[15]  P. Greengard,et al.  Generation of Alzheimer beta-amyloid protein in the trans-Golgi network in the apparent absence of vesicle formation. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[16]  D. Price,et al.  Presenilin 1 is required for Notch 1 and Dll1 expression in the paraxial mesoderm , 1997, Nature.

[17]  G J Williams,et al.  The Protein Data Bank: a computer-based archival file for macromolecular structures. , 1977, Journal of molecular biology.

[18]  Nobuhiro Suzuki,et al.  Amyloids and Are Generated Intracellularly in Cultured Human Neurons and Their Secretion Increases with Maturation (*) , 1996, The Journal of Biological Chemistry.

[19]  J. Hardy,et al.  Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1 , 1996, Nature.

[20]  L. Villa-komaroff,et al.  Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease. , 1989, Science.

[21]  C. Behl,et al.  Hydrogen peroxide mediates amyloid β protein toxicity , 1994, Cell.

[22]  D. Pollen,et al.  Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease , 1995, Nature.

[23]  X. Chen,et al.  RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease , 1996, Nature.

[24]  H. Wiśniewski,et al.  Secretion and accumulation of Alzheimer's β-protein by cultured vascular smooth muscle cells from old and young dogs , 1995, Brain Research.

[25]  J. Ávila,et al.  Analysis of microtubule-associated protein tau glycation in paired helical filaments. , 1994, The Journal of biological chemistry.

[26]  D. Kirschner,et al.  Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. , 1990, Science.

[27]  D. Selkoe,et al.  Mutation of the β-amyloid precursor protein in familial Alzheimer's disease increases β-protein production , 1992, Nature.

[28]  J. Zweier,et al.  Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid β-peptide , 1995, Nature Medicine.

[29]  D. Selkoe,et al.  Cellular processing of β-amyloid precursor protein and the genesis of amyloid β-peptide , 1993, Cell.

[30]  Allan I. Levey,et al.  Familial Alzheimer's Disease–Linked Presenilin 1 Variants Elevate Aβ1–42/1–40 Ratio In Vitro and In Vivo , 1996, Neuron.

[31]  M. Mattson,et al.  A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[32]  C. W. Scott,et al.  Glycated tau protein in Alzheimer disease: a mechanism for induction of oxidant stress. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[33]  E M Wijsman,et al.  A familial Alzheimer's disease locus on chromosome 1 , 1995, Science.

[34]  C. Kawas,et al.  Neuronal cell death in Alzheimer's disease correlates with apoE uptake and intracellular Abeta stabilization. , 1997, The Journal of clinical investigation.

[35]  A. Roses.  From genes to mechanisms to therapies: Lessons to be learned from neurological disorders , 1996, Nature Medicine.

[36]  D. Selkoe,et al.  Enhanced Production and Oligomerization of the 42-residue Amyloid β-Protein by Chinese Hamster Ovary Cells Stably Expressing Mutant Presenilins* , 1997, The Journal of Biological Chemistry.

[37]  B. Hyman,et al.  Alzheimer–associated presenilins 1 and 2 : Neuronal expression in brain and localization to intracellular membranes in mammalian cells , 1996, Nature Medicine.

[38]  S. Tonegawa,et al.  Skeletal and CNS Defects in Presenilin-1-Deficient Mice , 1997, Cell.

[39]  C. Masters,et al.  Intracellular production of beta A4 amyloid of Alzheimer's disease: modulation by phosphoramidon and lack of coupling to the secretion of the amyloid precursor protein. , 1995, Biochemistry.

[40]  J. Devereux,et al.  A comprehensive set of sequence analysis programs for the VAX , 1984, Nucleic Acids Res..

[41]  G. Schellenberg,et al.  Secreted amyloid β–protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease , 1996, Nature Medicine.

[42]  B. Yankner,et al.  Apoptosis and increased generation of reactive oxygen species in Down's syndrome neurons in vitro , 1995, Nature.

[43]  S. Younkin,et al.  Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. , 1993, Science.

[44]  J. Loike,et al.  Scavenger receptor-mediated adhesion of microglia to β-amyloid fibrils , 1996, Nature.

[45]  M. Matsumoto,et al.  Purification and Characterization of a Novel Stress Protein, the 150-kDa Oxygen-regulated Protein (ORP150), from Cultured Rat Astrocytes and Its Expression in Ischemic Mouse Brain (*) , 1996, The Journal of Biological Chemistry.

[46]  Y. Ihara,et al.  Intracellular Generation and Accumulation of Amyloid β-Peptide Terminating at Amino Acid 42* , 1997, The Journal of Biological Chemistry.

[47]  C. Glabe,et al.  Intracellular accumulation and resistance to degradation of the Alzheimer amyloid A4/beta protein. , 1992, Proceedings of the National Academy of Sciences of the United States of America.