Lipoprotein receptors and cholesterol in APP trafficking and proteolytic processing, implications for Alzheimer's disease.

Amyloid-beta (Abeta) peptide accumulation in the brain is central to the pathogenesis of Alzheimer's disease (AD). Abeta is produced through proteolytic processing of a transmembrane protein, beta-amyloid precursor protein (APP), by beta- and gamma-secretases. Mounting evidence has demonstrated that alterations in APP cellular trafficking and localization directly impact its processing to Abeta. Members of the low-density lipoprotein receptor family, including LRP, LRP1B, SorLA/LR11, and apoER2, interact with APP and regulate its endocytic trafficking. Additionally, APP trafficking and processing are greatly affected by cellular cholesterol content. In this review, we summarize the current understanding of the roles of lipoprotein receptors and cholesterol in APP trafficking and processing and their implication for AD pathogenesis and therapy.

[1]  Brett Chromy,et al.  Soluble oligomers of β amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus , 2002, Brain Research.

[2]  D. Selkoe,et al.  Mutagenesis identifies new signals for beta-amyloid precursor protein endocytosis, turnover, and the generation of secreted fragments, including Abeta42. , 1999, The Journal of biological chemistry.

[3]  H. Bock,et al.  Differential Glycosylation Regulates Processing of Lipoprotein Receptors by γ-Secretase* , 2003, Journal of Biological Chemistry.

[4]  B. Hyman,et al.  Low Density Lipoprotein Receptor-related Protein (LRP) Interacts with Presenilin 1 and Is a Competitive Substrate of the Amyloid Precursor Protein (APP) for γ-Secretase* , 2005, Journal of Biological Chemistry.

[5]  C. Haass,et al.  Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts , 2003, The Journal of cell biology.

[6]  D. Paris,et al.  Statins inhibit Aβ-neurotoxicity in vitro and Aβ-induced vasoconstriction and inflammation in rat aortae , 2002 .

[7]  Haipeng Cheng,et al.  Spatial segregation of gamma-secretase and substrates in distinct membrane domains. , 2005, The Journal of biological chemistry.

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

[9]  Jiyeon Lee,et al.  Adaptor Protein Sorting Nexin 17 Regulates Amyloid Precursor Protein Trafficking and Processing in the Early Endosomes* , 2008, Journal of Biological Chemistry.

[10]  D. Selkoe,et al.  A Critical Function for β-Amyloid Precursor Protein in Neuronal Migration Revealed by In Utero RNA Interference , 2007, The Journal of Neuroscience.

[11]  Yonghe Li,et al.  The Putative Tumor Suppressor LRP1B, a Novel Member of the Low Density Lipoprotein (LDL) Receptor Family, Exhibits Both Overlapping and Distinct Properties with the LDL Receptor-related Protein* , 2001, The Journal of Biological Chemistry.

[12]  Sascha Weggen,et al.  The cytoplasmic domain of the LDL receptor‐related protein regulates multiple steps in APP processing , 2002, The EMBO journal.

[13]  John Woulfe,et al.  Cholesterol retention in Alzheimer's brain is responsible for high β- and γ-secretase activities and Aβ production , 2008, Neurobiology of Disease.

[14]  S. Paul,et al.  Geranylgeranyl pyrophosphate stimulates gamma-secretase to increase the generation of Abeta and APP-CTFgamma. , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[15]  B. Hyman,et al.  Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid β-peptide , 2001, Nature Cell Biology.

[16]  P. Madsen,et al.  Activation and Functional Characterization of the Mosaic Receptor SorLA/LR11* , 2001, The Journal of Biological Chemistry.

[17]  W. Schneider,et al.  The Reelin Receptor ApoER2 Recruits JNK-interacting Proteins-1 and -2* , 2000, The Journal of Biological Chemistry.

[18]  L. Lue,et al.  Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. , 1999, The American journal of pathology.

[19]  D. Holtzman,et al.  Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. , 2008, The Journal of clinical investigation.

[20]  D. Strickland,et al.  LRP: a multifunctional scavenger and signaling receptor. , 2001, The Journal of clinical investigation.

[21]  D. C. Harris,et al.  Effects of apoE on neuronal signaling and APP processing in rodent brain , 2006, Brain Research.

[22]  Yonghe Li,et al.  The Low Density Lipoprotein Receptor-related Protein 1B Retains β-Amyloid Precursor Protein at the Cell Surface and Reduces Amyloid-β Peptide Production* , 2004, Journal of Biological Chemistry.

[23]  M. Citron,et al.  Strategies for disease modification in Alzheimer's disease , 2004, Nature Reviews Neuroscience.

[24]  B. Hyman,et al.  The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel β-Secretase (BACE1) Substrate* , 2005, Journal of Biological Chemistry.

[25]  E. Weeber,et al.  The generation and function of soluble apoE receptors in the CNS , 2006, Molecular Neurodegeneration.

[26]  D. Selkoe,et al.  Cell surface presenilin-1 participates in the gamma-secretase-like proteolysis of Notch. , 1999, The Journal of biological chemistry.

[27]  G. Celesia,et al.  Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. , 2000, Archives of neurology.

[28]  K. G. Coleman,et al.  Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. , 1997, Science.

[29]  G. Bu,et al.  LRP in Amyloid‐β Production and Metabolism , 2006 .

[30]  D. Strickland,et al.  The Cellular Internalization and Degradation of Hepatic Lipase Is Mediated by Low Density Lipoprotein Receptor-related Protein and Requires Cell Surface Proteoglycans (*) , 1995, The Journal of Biological Chemistry.

[31]  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.

[32]  E. Kojro,et al.  Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α-secretase ADAM 10 , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[33]  A. Jauch,et al.  Alteration of the LRP1B Gene Region Is Associated with High Grade of Urothelial Cancer , 2002, Laboratory Investigation.

[34]  N. Inestrosa,et al.  ApoER2 is Endocytosed by a Clathrin‐Mediated Process Involving the Adaptor Protein Dab2 Independent of its Rafts' Association , 2005, Traffic.

[35]  G. Bu,et al.  Receptor-associated protein: a specialized chaperone and antagonist for members of the LDL receptor gene family. , 1998, Current opinion in lipidology.

[36]  D. Mangelsdorf,et al.  LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[37]  Y. Matsuoka,et al.  DAB1 and Reelin Effects on Amyloid Precursor Protein and ApoE Receptor 2 Trafficking and Processing* , 2006, Journal of Biological Chemistry.

[38]  R. Wattiaux,et al.  Identification of HE1 as the second gene of Niemann-Pick C disease. , 2000, Science.

[39]  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.

[40]  D. Strickland,et al.  Sequence identity between the alpha 2-macroglobulin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor. , 1990, The Journal of biological chemistry.

[41]  P. Schwille,et al.  Lipids as Modulators of Proteolytic Activity of BACE , 2005, Journal of Biological Chemistry.

[42]  R. Deane,et al.  LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms. , 2004, Neuron.

[43]  D. Spasic,et al.  Building γ-secretase – the bits and pieces , 2008, Journal of Cell Science.

[44]  Peter Tontonoz,et al.  Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors , 2007, Proceedings of the National Academy of Sciences.

[45]  P. Tontonoz,et al.  Liver X receptors as integrators of metabolic and inflammatory signaling. , 2006, The Journal of clinical investigation.

[46]  P. Zandi,et al.  Cholesterol and Alzheimer's disease—is there a relation? , 2006, Mechanisms of Ageing and Development.

[47]  B. de Strooper,et al.  Presenilin 1 Controls γ-Secretase Processing of Amyloid Precursor Protein in Pre-Golgi Compartments of Hippocampal Neurons , 1999, The Journal of cell biology.

[48]  W Blaine Stine,et al.  Soluble oligomers of beta amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus. , 2002, Brain research.

[49]  P. Greengard,et al.  Identification of the Alzheimer beta/A4 amyloid precursor protein in clathrin-coated vesicles purified from PC12 cells. , 1993, The Journal of biological chemistry.

[50]  Yonghe Li,et al.  The YXXL Motif, but Not the Two NPXY Motifs, Serves as the Dominant Endocytosis Signal for Low Density Lipoprotein Receptor-related Protein* , 2000, The Journal of Biological Chemistry.

[51]  B. Strooper,et al.  Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[52]  G. Rebeck,et al.  Regulated Proteolysis of APP and ApoE Receptors , 2008, Molecular Neurobiology.

[53]  Yonghe Li,et al.  Low Density Lipoprotein (LDL) Receptor-related Protein 1B Impairs Urokinase Receptor Regeneration on the Cell Surface and Inhibits Cell Migration* , 2002, The Journal of Biological Chemistry.

[54]  B. Hyman,et al.  Interaction of the Cytosolic Domains of sorLA/LR11 with the Amyloid Precursor Protein (APP) and β-Secretase β-Site APP-Cleaving Enzyme , 2006, The Journal of Neuroscience.

[55]  M. Staufenbiel,et al.  Expression profiling in APP23 mouse brain: inhibition of Aβ amyloidosis and inflammation in response to LXR agonist treatment , 2007, Molecular Neurodegeneration.

[56]  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.

[57]  J. H. Boo,et al.  Lovastatin enhances Aβ production and senile plaque deposition in female Tg2576 mice , 2003, Neurobiology of Aging.

[58]  M. Mercken,et al.  Presenilin Redistribution Associated with Aberrant Cholesterol Transport Enhances β-Amyloid Production In Vivo , 2003, The Journal of Neuroscience.

[59]  N. Hooper,et al.  Cleavage of Alzheimer's amyloid precursor protein by alpha-secretase occurs at the surface of neuronal cells. , 1999, Biochemistry.

[60]  Y. Ihara,et al.  Accumulation and Aggregation of Amyloid β-Protein in Late Endosomes of Niemann-Pick Type C Cells* , 2001, The Journal of Biological Chemistry.

[61]  Z. Fu,et al.  FE65 Interaction with the ApoE Receptor ApoEr2* , 2006, Journal of Biological Chemistry.

[62]  J. Koenigsknecht-Talboo,et al.  Mechanisms of Statin-mediated Inhibition of Small G-protein Function* , 2005, Journal of Biological Chemistry.

[63]  H. Bock,et al.  Lipoprotein receptors in the nervous system. , 2002, Annual review of biochemistry.

[64]  Maria D. Guillily,et al.  Oxysterol-binding protein-1 (OSBP1) modulates processing and trafficking of the amyloid precursor protein , 2008, Molecular Neurodegeneration.

[65]  N. Greig,et al.  Cholesterol and Alzheimer's disease: clinical and experimental models suggest interactions of different genetic, dietary and environmental risk factors. , 2004, Current drug targets.

[66]  R. Katzman.,et al.  Modulation of amyloid beta-protein clearance and Alzheimer's disease susceptibility by the LDL receptor-related protein pathway. , 2000, The Journal of clinical investigation.

[67]  J. Treanor,et al.  Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. , 1999, Science.

[68]  D. Selkoe,et al.  Mutagenesis Identifies New Signals for β-Amyloid Precursor Protein Endocytosis, Turnover, and the Generation of Secreted Fragments, Including Aβ42* , 1999, The Journal of Biological Chemistry.

[69]  T. Willnow,et al.  Cellular signalling by lipoprotein receptors , 2000, Current opinion in lipidology.

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

[71]  G. Rebeck,et al.  Regulation of ApoE receptor proteolysis by ligand binding. , 2005, Brain research. Molecular brain research.

[72]  R. Pepperkok,et al.  Inhibition of Intracellular Cholesterol Transport Alters Presenilin Localization and Amyloid Precursor Protein Processing in Neuronal Cells , 2002, The Journal of Neuroscience.

[73]  K. Beyreuther,et al.  Independent Inhibition of Alzheimer Disease β- and γ-Secretase Cleavage by Lowered Cholesterol Levels* , 2008, Journal of Biological Chemistry.

[74]  N. Inestrosa,et al.  ApoER2 expression increases Aβ production while decreasing Amyloid Precursor Protein (APP) endocytosis: Possible role in the partitioning of APP into lipid rafts and in the regulation of γ-secretase activity , 2007, Molecular Neurodegeneration.

[75]  J. Minna,et al.  LRP-DIT, a putative endocytic receptor gene, is frequently inactivated in non-small cell lung cancer cell lines. , 2000, Cancer research.

[76]  M. Gallagher,et al.  A specific amyloid-β protein assembly in the brain impairs memory , 2006, Nature.

[77]  D. Selkoe.  Deciphering the genesis and fate of amyloid beta-protein yields novel therapies for Alzheimer disease. , 2002, The Journal of clinical investigation.

[78]  O. Myklebost,et al.  Surface location and high affinity for calcium of a 500‐kd liver membrane protein closely related to the LDL‐receptor suggest a physiological role as lipoprotein receptor. , 1988, The EMBO journal.

[79]  Xiangyuan He,et al.  Apolipoprotein receptor 2 and X11 alpha/beta mediate apolipoprotein E-induced endocytosis of amyloid-beta precursor protein and beta-secretase, leading to amyloid-beta production. , 2007, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[80]  Ramin Homayouni,et al.  Disabled-1 Binds to the Cytoplasmic Domain of Amyloid Precursor-Like Protein 1 , 1999, The Journal of Neuroscience.

[81]  J. S. Owen,et al.  Localization of apolipoprotein E receptor 2 to caveolae in the plasma membrane. , 2001, Journal of lipid research.

[82]  D. Selkoe,et al.  Cell Surface Presenilin-1 Participates in the γ-Secretase-like Proteolysis of Notch* , 1999, The Journal of Biological Chemistry.

[83]  L. V. Van Eldik,et al.  ApoE and Abeta1-42 interactions: effects of isoform and conformation on structure and function. , 2004, Journal of molecular neuroscience : MN.

[84]  G. Rebeck,et al.  Apolipoprotein E decreases tau kinases and phospho-tau levels in primary neurons , 2006, Molecular Neurodegeneration.

[85]  D. Riddell,et al.  Compartmentalization of β-secretase (Asp2) into low-buoyant density, noncaveolar lipid rafts , 2001, Current Biology.

[86]  L. Lue,et al.  Soluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer’s Disease , 1999 .

[87]  M. Staufenbiel,et al.  Lack of ABCA1 Considerably Decreases Brain ApoE Level and Increases Amyloid Deposition in APP23 Mice* , 2005, Journal of Biological Chemistry.

[88]  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.

[89]  Hui Zheng,et al.  Molecular Neurodegeneration BioMed Central Review The amyloid precursor protein: beyond amyloid , 2006 .

[90]  Huaxi Xu,et al.  Pathological and physiological functions of presenilins , 2006, Molecular Neurodegeneration.

[91]  L. Parisiadou,et al.  Expression of mDab1 promotes the stability and processing of amyloid precursor protein and this effect is counteracted by X11α , 2007, Neurobiology of Aging.

[92]  H. Lipp,et al.  Mice with Combined Gene Knock-Outs Reveal Essential and Partially Redundant Functions of Amyloid Precursor Protein Family Members , 2000, The Journal of Neuroscience.

[93]  J. Hardy,et al.  The Amyloid Hypothesis of Alzheimer ’ s Disease : Progress and Problems on the Road to Therapeutics , 2009 .

[94]  P. Wong,et al.  Association of γ-Secretase with Lipid Rafts in Post-Golgi and Endosome Membranes* , 2004, Journal of Biological Chemistry.

[95]  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.

[96]  E. V. van Donselaar,et al.  Recycling Compartments and the Internal Vesicles of Multivesicular Bodies Harbor Most of the Cholesterol Found in the Endocytic Pathway , 2003, Traffic.

[97]  B. Hyman,et al.  Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[98]  A. Delacourte,et al.  Neuronal membrane cholesterol loss enhances amyloid peptide generation , 2004, The Journal of cell biology.

[99]  Doo Yeon Kim,et al.  Presenilin/γ‐secretase activity regulates protein clearance from the endocytic recycling compartment , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[100]  W. Schneider,et al.  Elements of Neural Adhesion Molecules and a Yeast Vacuolar Protein Sorting Receptor Are Present in a Novel Mammalian Low Density Lipoprotein Receptor Family Member* , 1996, The Journal of Biological Chemistry.

[101]  C. Masters,et al.  Soluble pool of Aβ amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease , 1999, Annals of neurology.

[102]  W. Walker,et al.  Summary and future directions , 1992, The Journal of Pediatrics.

[103]  A. Soutar,et al.  Expression in vitro of alternatively spliced variants of the messenger RNA for human apolipoprotein E receptor-2 identified in human tissues by ribonuclease protection assays. , 1999, European journal of biochemistry.

[104]  B. Strooper,et al.  Presenilins: molecular switches between proteolysis and signal transduction , 1999, Trends in Neurosciences.

[105]  S. Paul,et al.  A liver X receptor and retinoid X receptor heterodimer mediates apolipoprotein E expression, secretion and cholesterol homeostasis in astrocytes , 2004, Journal of neurochemistry.

[106]  A. Tall,et al.  Expression of Liver X Receptor Target Genes Decreases Cellular Amyloid β Peptide Secretion* , 2003, Journal of Biological Chemistry.

[107]  Joachim Herz,et al.  Reelin Activates Src Family Tyrosine Kinases in Neurons , 2003, Current Biology.

[108]  N. Hooper,et al.  Exclusively targeting β-secretase to lipid rafts by GPI-anchor addition up-regulates β-site processing of the amyloid precursor protein , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[109]  Yun Bai,et al.  Activation of β2-adrenergic receptor stimulates γ-secretase activity and accelerates amyloid plaque formation , 2006, Nature Medicine.

[110]  H. Vanderstichele,et al.  The discrepancy between presenilin subcellular localization and γ-secretase processing of amyloid precursor protein , 2001, The Journal of cell biology.

[111]  Ramin Homayouni,et al.  Reelin Is a Ligand for Lipoprotein Receptors , 1999, Neuron.

[112]  C. Ackerley,et al.  Presenilin-1, Nicastrin, Amyloid Precursor Protein, and γ-Secretase Activity Are Co-localized in the Lysosomal Membrane* , 2003, Journal of Biological Chemistry.

[113]  R. Turner,et al.  Adaptor protein interactions: modulators of amyloid precursor protein metabolism and Alzheimer's disease risk? , 2004, Experimental Neurology.

[114]  U. Laufs,et al.  Pleiotropic effects of HMG-CoA reductase inhibitors , 2002, Basic Research in Cardiology.

[115]  D. Selkoe.  Alzheimer's disease: genes, proteins, and therapy. , 2001, Physiological reviews.

[116]  N. Hooper,et al.  ADAMs family members as amyloid precursor protein alpha-secretases. , 2003, Journal of neuroscience research.

[117]  Yun Bai,et al.  Activation of beta2-adrenergic receptor stimulates gamma-secretase activity and accelerates amyloid plaque formation. , 2006, Nature medicine.

[118]  Matthew P. Frosch,et al.  The ACAT Inhibitor CP-113,818 Markedly Reduces Amyloid Pathology in a Mouse Model of Alzheimer's Disease , 2010, Neuron.

[119]  Katrin Marcus,et al.  The amyloid precursor protein intracellular domain (AICD) as modulator of gene expression, apoptosis, and cytoskeletal dynamics—Relevance for Alzheimer's disease , 2008, Progress in Neurobiology.

[120]  D. Holtzman,et al.  Deletion of Abca1 Increases Aβ Deposition in the PDAPP Transgenic Mouse Model of Alzheimer Disease* , 2005, Journal of Biological Chemistry.

[121]  J. Herz,et al.  Proteolytic Processing of Low Density Lipoprotein Receptor-related Protein Mediates Regulated Release of Its Intracellular Domain* , 2002, The Journal of Biological Chemistry.

[122]  Matthew P. Frosch,et al.  The ACAT Inhibitor CP-113,818 Markedly Reduces Amyloid Pathology in a Mouse Model of Alzheimer's Disease , 2004, Neuron.

[123]  W. K. Cullen,et al.  Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo , 2002, Nature.

[124]  H. Geuze,et al.  Slow endocytosis of the LDL receptor-related protein 1B: implications for a novel cytoplasmic tail conformation. , 2007, Experimental cell research.

[125]  Haipeng Cheng,et al.  Spatial Segregation of γ-Secretase and Substrates in Distinct Membrane Domains* , 2005, Journal of Biological Chemistry.

[126]  A. Levey,et al.  The Lipoprotein Receptor LR11 Regulates Amyloid β Production and Amyloid Precursor Protein Traffic in Endosomal Compartments , 2006, The Journal of Neuroscience.

[127]  Yonghe Li,et al.  The low density lipoprotein receptor-related protein 1B retains beta-amyloid precursor protein at the cell surface and reduces amyloid-beta peptide production. , 2004, The Journal of biological chemistry.

[128]  J. Woo,et al.  Low-density lipoprotein receptor-related protein 8 (apolipoprotein E receptor 2) gene polymorphisms in Alzheimer's disease , 2002, Neuroscience Letters.

[129]  L. Muglia,et al.  Amyloid Precursor Protein Regulates Brain Apolipoprotein E and Cholesterol Metabolism through Lipoprotein Receptor LRP1 , 2007, Neuron.

[130]  L. Mucke,et al.  Reelin Depletion in the Entorhinal Cortex of Human Amyloid Precursor Protein Transgenic Mice and Humans with Alzheimer's Disease , 2007, The Journal of Neuroscience.

[131]  N. Tommerup,et al.  Molecular Characterization of a Novel Human Hybrid-type Receptor That Binds the α2-Macroglobulin Receptor-associated Protein* , 1996, The Journal of Biological Chemistry.

[132]  Joachim Herz,et al.  Direct Binding of Reelin to VLDL Receptor and ApoE Receptor 2 Induces Tyrosine Phosphorylation of Disabled-1 and Modulates Tau Phosphorylation , 1999, Neuron.

[133]  D. Holtzman,et al.  Apolipoprotein E and Low Density Lipoprotein Receptor-related Protein Facilitate Intraneuronal Aβ42 Accumulation in Amyloid Model Mice* , 2006, Journal of Biological Chemistry.

[134]  J. Borg,et al.  Interaction of Cytosolic Adaptor Proteins with Neuronal Apolipoprotein E Receptors and the Amyloid Precursor Protein* , 1998, The Journal of Biological Chemistry.

[135]  S. DeKosky,et al.  22R-Hydroxycholesterol and 9-cis-Retinoic Acid Induce ATP-binding Cassette Transporter A1 Expression and Cholesterol Efflux in Brain Cells and Decrease Amyloid β Secretion* , 2003, The Journal of Biological Chemistry.

[136]  D. Holtzman,et al.  Increased soluble amyloid-beta peptide and memory deficits in amyloid model mice overexpressing the low-density lipoprotein receptor-related protein. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[137]  J. Poirier,et al.  The apoE receptor apoER2 is involved in the maintenance of efficient synaptic plasticity , 2005, Neurobiology of Aging.

[138]  G. Bu,et al.  LRP in amyloid-beta production and metabolism. , 2006, Annals of the New York Academy of Sciences.

[139]  Peter J. Lenting,et al.  LRP/Amyloid β-Peptide Interaction Mediates Differential Brain Efflux of Aβ Isoforms , 2004, Neuron.

[140]  Y. Matsuoka,et al.  F-Spondin Interaction with the Apolipoprotein E Receptor ApoEr2 Affects Processing of Amyloid Precursor Protein , 2005, Molecular and Cellular Biology.

[141]  K. Lunetta,et al.  The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease , 2007, Nature Genetics.

[142]  Mushfiquddin Khan,et al.  Lovastatin inhibits amyloid precursor protein (APP) β‐cleavage through reduction of APP distribution in Lubrol WX extractable low density lipid rafts , 2008, Journal of neurochemistry.

[143]  R. Vassar,et al.  Molecular Neurodegeneration BioMed Central Review The Alzheimer's disease β-secretase enzyme, BACE1 , 2007 .

[144]  R. Hammer,et al.  ApoE Receptor 2 Controls Neuronal Survival in the Adult Brain , 2006, Current Biology.

[145]  C. Haass,et al.  SorLA Signaling by Regulated Intramembrane Proteolysis* , 2006, Journal of Biological Chemistry.

[146]  G. Landreth,et al.  Statins Reduce Amyloid-β Production through Inhibition of Protein Isoprenylation* , 2007, Journal of Biological Chemistry.

[147]  S. Paul,et al.  Geranylgeranyl pyrophosphate stimulates γ‐secretase to increase the generation of Aβ and APP‐CTFγ , 2008 .

[148]  B. Strooper,et al.  Regulation of cholesterol and sphingomyelin metabolism by amyloid-β and presenilin , 2005, Nature Cell Biology.

[149]  B. Strooper,et al.  Proteolytic processing and cell biological functions of the amyloid precursor protein. , 2000, Journal of cell science.

[150]  G. Bu,et al.  Modulation of β-amyloid precursor protein trafficking and processing by the low density lipoprotein receptor family , 2006, Molecular Neurodegeneration.

[151]  L. Liscum,et al.  The intracellular transport of low density lipoprotein-derived cholesterol is inhibited in Chinese hamster ovary cells cultured with 3-beta-[2-(diethylamino)ethoxy]androst-5-en-17-one. , 1989, The Journal of biological chemistry.

[152]  Shaomin Li,et al.  Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory , 2008, Nature Medicine.

[153]  J. Buxbaum,et al.  Atorvastatin‐induced activation of Alzheimer's α secretase is resistant to standard inhibitors of protein phosphorylation‐regulated ectodomain shedding , 2004, Journal of neurochemistry.

[154]  S. Squazzo,et al.  Evidence that production and release of amyloid beta-protein involves the endocytic pathway. , 1994, The Journal of biological chemistry.

[155]  D. Selkoe,et al.  Cell biology of the amyloid beta-protein precursor and the mechanism of Alzheimer's disease. , 1994, Annual review of cell biology.

[156]  A. Schwartz,et al.  Dissection of receptor folding and ligand-binding property with functional minireceptors of LDL receptor-related protein. , 2001, Journal of cell science.

[157]  Irwin D Kuntz,et al.  Apolipoprotein (apo) E4 enhances amyloid beta peptide production in cultured neuronal cells: apoE structure as a potential therapeutic target. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[158]  T. Bird,et al.  Intracellular accumulation of amyloidogenic fragments of amyloid-beta precursor protein in neurons with Niemann-Pick type C defects is associated with endosomal abnormalities. , 2004, The American journal of pathology.

[159]  Yonghe Li,et al.  Differential Functions of Members of the Low Density Lipoprotein Receptor Family Suggested by Their Distinct Endocytosis Rates* , 2001, The Journal of Biological Chemistry.

[160]  A. Levey,et al.  Loss of apolipoprotein E receptor LR11 in Alzheimer disease. , 2004, Archives of neurology.

[161]  H Jick,et al.  Statins and the risk of dementia , 2000, The Lancet.

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

[163]  M. Mercken,et al.  A Cholesterol-Lowering Drug Reduces β-Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease , 2001, Neurobiology of Disease.

[164]  D. C. Harris,et al.  Multiple pathways of apolipoprotein E signaling in primary neurons , 2005, Journal of neurochemistry.

[165]  Michela Gallagher,et al.  A specific amyloid-beta protein assembly in the brain impairs memory. , 2006, Nature.

[166]  L. K. Baker,et al.  Oligomeric and Fibrillar Species of Amyloid-β Peptides Differentially Affect Neuronal Viability* , 2002, The Journal of Biological Chemistry.

[167]  M. Ehlers,et al.  Apolipoprotein E Receptor 2 Interactions with the N-Methyl-D-aspartate Receptor* , 2006, Journal of Biological Chemistry.

[168]  L. Lue,et al.  Cholesterol retention in Alzheimer's brain is responsible for high beta- and gamma-secretase activities and Abeta production. , 2008, Neurobiology of disease.

[169]  Yonghe Li,et al.  Rapid Endocytosis of the Low Density Lipoprotein Receptor-related Protein Modulates Cell Surface Distribution and Processing of the β-Amyloid Precursor Protein* , 2005, Journal of Biological Chemistry.

[170]  N. Hooper,et al.  ADAMs family members as amyloid precursor protein α‐secretases , 2003 .

[171]  M. Hennerici,et al.  Simvastatin strongly reduces levels of Alzheimer's disease beta -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[172]  P. Wong,et al.  Association of gamma-secretase with lipid rafts in post-Golgi and endosome membranes. , 2004, The Journal of biological chemistry.

[173]  B. Hyman,et al.  Demonstration by FRET of BACE interaction with the amyloid precursor protein at the cell surface and in early endosomes , 2003, Journal of Cell Science.

[174]  E. Komives,et al.  Two apolipoprotein E mimetic peptides, ApoE(130-149) and ApoE(141-155)2, bind to LRP1. , 2004, Biochemistry.

[175]  C. Bergmann,et al.  Simvastatin strongly reduces levels of Alzheimer's disease β-amyloid peptides Aβ42 and Aβ40 in vitro and in vivo , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[176]  E. Komives,et al.  All three LDL receptor homology regions of the LDL receptor-related protein bind multiple ligands. , 2003, Biochemistry.

[177]  Vanessa Schmidt,et al.  Molecular dissection of the interaction between amyloid precursor protein and its neuronal trafficking receptor SorLA/LR11. , 2006, Biochemistry.

[178]  D. Selkoe,et al.  Presenilin‐1 Exists in Both Pre‐ and Post‐Golgi Compartments and Recycles Via COPI‐Coated Membranes , 2003, Traffic.

[179]  B. Margolis,et al.  The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein , 1996, Molecular and cellular biology.

[180]  K. Goto,et al.  Human Apolipoprotein E Receptor 2 , 1996, The Journal of Biological Chemistry.

[181]  R. Hammer,et al.  Functional Dissection of Reelin Signaling by Site-Directed Disruption of Disabled-1 Adaptor Binding to Apolipoprotein E Receptor 2: Distinct Roles in Development and Synaptic Plasticity , 2006, The Journal of Neuroscience.

[182]  J. Gruenberg,et al.  Membrane Dynamics in Endocytosis: Structure–Function Relationship , 2000, Traffic.

[183]  M. Frotscher,et al.  Modulation of Synaptic Plasticity and Memory by Reelin Involves Differential Splicing of the Lipoprotein Receptor Apoer2 , 2005, Neuron.

[184]  K. Chin,et al.  Frequent Silencing of Low Density Lipoprotein Receptor-Related Protein 1B (LRP1B) Expression by Genetic and Epigenetic Mechanisms in Esophageal Squamous Cell Carcinoma , 2004, Cancer Research.