A Protective Role of the Low Density Lipoprotein Receptor-related Protein against Amyloid β-Protein Toxicity*

In order to delineate the neuroprotective role of the low density lipoprotein receptor-related protein (LRP) against amyloid β-protein toxicity, studies were performed in C6 cells challenged with amyloid β-protein in the presence or absence of activated α2-macroglobulin. Toxicity was assessed via two cell viability assays. We found that this endocytic receptor conferred protection against amyloid β-protein toxicity in the presence of activated α2-macroglobulin and its down-regulation via inhibition by receptor-associated protein or transfection of cells with presenilin 1, increased susceptibility to amyloid β-protein toxicity. Increased surface LRP immunoreactivity in response to amyloid β-protein challenge was associated with increased translocation of LRP from the endoplasmic reticulum to the surface, rather than from increased mRNA or protein expression. Furthermore, this translocation of LRP to the surface was mediated by a calcium/calmodulin protein kinase II-dependent signaling pathway. These studies provide evidence for a protective role of LRP against amyloid β-protein toxicity and may explain the aggressive nature of presenilin-1 mutation in familial Alzheimer's disease.

[1]  B. Hyman,et al.  Modulation of beta-amyloid precursor protein processing by the low density lipoprotein receptor-related protein (LRP). Evidence that LRP contributes to the pathogenesis of Alzheimer's disease. , 2000, The Journal of biological chemistry.

[2]  L. Mucke,et al.  Elimination of the class A scavenger receptor does not affect amyloid plaque formation or neurodegeneration in transgenic mice expressing human amyloid protein precursors. , 1999, The American journal of pathology.

[3]  B. Hyman,et al.  α2‐Macroglobulin Enhances the Clearance of Endogenous Soluble β‐Amyloid Peptide via Low‐Density Lipoprotein Receptor‐Related Protein in Cortical Neuron , 1999 .

[4]  E. Masliah,et al.  Aberrant Presenilin-1 Expression Downregulates LDL Receptor-Related Protein (LRP): Is LRP Central to Alzheimer's Disease Pathogenesis? , 1999, Molecular and Cellular Neuroscience.

[5]  M. Mattson,et al.  Expression of calbindin-D28k in C6 glial cells stabilizes intracellular calcium levels and protects against apoptosis induced by calcium ionophore and amyloid beta-peptide. , 1999, Brain research. Molecular brain research.

[6]  R. Brasseur,et al.  β‐Amyloid Peptide Interacts Specifically with the Carboxyl‐Terminal Domain of Human Apolipoprotein E , 1999, Journal of Neurochemistry.

[7]  W. Markesbery,et al.  Oxidative Alterations in Alzheimer's Disease , 1999, Brain pathology.

[8]  E. Masliah,et al.  Caspase Dependent DNA Fragmentation Might Be Associated with Excitotoxicity in Alzheimer Disease , 1998, Journal of neuropathology and experimental neurology.

[9]  M. Stern,et al.  Increased transmitter release and aberrant synapse morphology in a Drosophila calmodulin mutant. , 1998, Genetics.

[10]  Steven M. Horvath,et al.  Alpha-2 macroglobulin is genetically associated with Alzheimer disease , 1998, Nature Genetics.

[11]  J. Miguel-Hidalgo,et al.  β-Amyloid(1–40)-induced neurodegeneration in the rat hippocampal neurons of the CA1 subfield , 1998, Acta Neuropathologica.

[12]  O. Khorkova,et al.  α2-macroglobulin associates with β-amyloid peptide and prevents fibril formation , 1998 .

[13]  E. Gruenstein,et al.  Identification of a neuronal endocytic pathway activated by an apolipoprotein E (apoE) receptor binding peptide , 1997, Brain Research.

[14]  D. Holtzman,et al.  α2‐Macroglobulin Complexes with and Mediates the Endocytosis of β‐Amyloid Peptide via Cell Surface Low‐Density Lipoprotein Receptor‐Related Protein , 1997 .

[15]  F. Valdivieso,et al.  Apolipoprotein E forms stable complexes with recombinant Alzheimer's disease beta-amyloid precursor protein. , 1997, The Biochemical journal.

[16]  R. Dodel,et al.  α2‐Macroglobulin as a β‐Amyloid Peptide‐Binding Plasma Protein , 1997 .

[17]  L. Thal,et al.  Genetic association of the low-density lipoprotein receptor-related protein gene (LRP), and apolipoprotein E receptor, with late-onset Alzheimer's disease , 1997, Neurology.

[18]  G. Getz,et al.  Association of human, rat, and rabbit apolipoprotein E with β‐amyloid , 1997, Journal of neuroscience research.

[19]  M. Colombo,et al.  Calmodulin Regulates Endosome Fusion* , 1997, The Journal of Biological Chemistry.

[20]  Kevin Taddei,et al.  Increased plasma apolipoprotein E (apoE) levels in Alzheimer's disease , 1997, Neuroscience Letters.

[21]  C. Moore,et al.  Ca2+/calmodulin-dependent protein kinase II phosphorylation of the presynaptic protein synapsin I is persistently increased during long-term potentiation. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[22]  A. Fagan,et al.  Apolipoprotein E-containing High Density Lipoprotein Promotes Neurite Outgrowth and Is a Ligand for the Low Density Lipoprotein Receptor-related Protein* , 1996, The Journal of Biological Chemistry.

[23]  C. Glabe,et al.  Cell surface APP751 forms complexes with protease nexin 2 ligands and is internalized via the low density lipoprotein receptor-related protein (LRP) , 1996, Brain Research.

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

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

[26]  R. Tanzi,et al.  REVIEWThe Gene Defects Responsible for Familial Alzheimer's Disease , 1996, Neurobiology of Disease.

[27]  L. Mucke,et al.  Levels and Alternative Splicing of Amyloid β Protein Precursor (APP) Transcripts in Brains of APP Transgenic Mice and Humans with Alzheimer's Disease (*) , 1995, The Journal of Biological Chemistry.

[28]  B. Hyman,et al.  LDL receptor-related protein, a multifunctional ApoE receptor, binds secreted β-amyloid precursor protein and mediates its degradation , 1995, Cell.

[29]  R. Czekay,et al.  The expression of megalin (gp330) and LRP diverges during F9 cell differentiation. , 1995, Journal of cell science.

[30]  Dominique Muller,et al.  Increased Phosphorylation of Ca/Calmodulin-dependent Protein Kinase II and Its Endogenous Substrates in the Induction of Long Term Potentiation (*) , 1995, The Journal of Biological Chemistry.

[31]  F. Licastro,et al.  Increased serum α 1-antichymotrypsin in patients with probable Alzheimer's disease: an acute phase reactant without the peripheral acute phase response , 1995, Journal of Neuroimmunology.

[32]  B. Hyman,et al.  Multiple, diverse senile plaque–associated proteins are ligands of an apolipoprotein e receptor, the α2‐macroglobulin receptor/low‐density‐lipoprotein receptor—related protein , 1995, Annals of neurology.

[33]  D. Strickland,et al.  The 39-kDa Receptor-associated Protein Modulates Lipoprotein Catabolism by Binding to LDL Receptors (*) , 1995, The Journal of Biological Chemistry.

[34]  W. Hunziker.  The calmodulin antagonist W-7 affects transcytosis, lysosomal transport, and recycling but not endocytosis. , 1994, The Journal of biological chemistry.

[35]  K. Mostov,et al.  The calmodulin antagonist, W-13, alters transcytosis, recycling, and the morphology of the endocytic pathway in Madin-Darby canine kidney cells. , 1994, The Journal of biological chemistry.

[36]  S. Vandenberg,et al.  Expression of α2‐macroglobulin receptor/low density lipoprotein receptor‐related protein is increased in reactive and neoplastic glial cells , 1994, FEBS letters.

[37]  B. Hyman,et al.  Apolipoprotein E in sporadic Alzheimer's disease: Allelic variation and receptor interactions , 1993, Neuron.

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

[39]  M. Farquhar,et al.  Identification of a cell line that expresses a cell surface and a soluble form of the gp330/receptor-associated protein (RAP) Heymann nephritis antigenic complex. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[40]  I Nicoletti,et al.  A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. , 1991, Journal of immunological methods.

[41]  P. Greengard,et al.  Effects of synapsin I and calcium/calmodulin-dependent protein kinase II on spontaneous neurotransmitter release in the squid giant synapse. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[42]  U. Beisiegel,et al.  The LDL–receptor–related protein, LRP, is an apolipoprotein E-binding protein , 1989, Nature.

[43]  R. Nicoll,et al.  An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation , 1989, Nature.

[44]  M. Beal,et al.  The neurotoxicity of amyloid beta protein in aged primates. , 1998, Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis.

[45]  T. Feng.  The involvement of PKC and multifunctional CaM kinase II of the postsynaptic neuron in induction and maintenance of long-term potentiation. , 1995, Progress in brain research.