LRP/Amyloid β-Peptide Interaction Mediates Differential Brain Efflux of Aβ Isoforms

Abstract LRP (low-density lipoprotein receptor-related protein) is linked to Alzheimer's disease (AD). Here, we report amyloid β-peptide Aβ40 binds to immobilized LRP clusters II and IV with high affinity (K d = 0.6–1.2 nM) compared to Aβ42 and mutant Aβ, and LRP-mediated Aβ brain capillary binding, endocytosis, and transcytosis across the mouse blood-brain barrier are substantially reduced by the high β sheet content in Aβ and deletion of the receptor-associated protein gene. Despite low Aβ production in the brain, transgenic mice expressing low LRP-clearance mutant Aβ develop robust Aβ cerebral accumulations much earlier than Tg-2576 Aβ-overproducing mice. While Aβ does not affect LRP internalization and synthesis, it promotes proteasome-dependent LRP degradation in endothelium at concentrations >1 μM, consistent with reduced brain capillary LRP levels in Aβ-accumulating transgenic mice, AD, and patients with cerebrovascular β-amyloidosis. Thus, low-affinity LRP/Aβ interaction and/or Aβ-induced LRP loss at the BBB mediate brain accumulation of neurotoxic Aβ.

[1]  José A Fernández,et al.  Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective , 2003, Nature Medicine.

[2]  S. Younkin,et al.  Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice , 1996, Science.

[3]  B. Strooper,et al.  FAD mutant PS-1 gene-targeted mice: increased Aβ42 and Aβ deposition without APP overproduction , 2002, Neurobiology of Aging.

[4]  E. Masliah,et al.  Increased Extracellular Amyloid Deposition and Neurodegeneration in Human Amyloid Precursor Protein Transgenic Mice Deficient in Receptor-Associated Protein , 2002, The Journal of Neuroscience.

[5]  Ann Marie Schmidt,et al.  RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain , 2003, Nature Medicine.

[6]  I. Lieberburg,et al.  Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. , 1990, Science.

[7]  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 .

[8]  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.

[9]  R J Miller,et al.  Isoform-Specific Effect of Apolipoprotein E on Cell Survival and β-Amyloid-Induced Toxicity in Rat Hippocampal Pyramidal Neuronal Cultures , 1998, The Journal of Neuroscience.

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

[11]  D. Holtzman,et al.  Brain to Plasma Amyloid-β Efflux: a Measure of Brain Amyloid Burden in a Mouse Model of Alzheimer's Disease , 2002, Science.

[12]  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.

[13]  G. Bu,et al.  The roles of receptor-associated protein (RAP) as a molecular chaperone for members of the LDL receptor family. , 2001, International review of cytology.

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

[15]  J. Hardy,et al.  Association between coding variability in the LRP gene and the risk of late-onset Alzheimer’s disease , 1999, Human Genetics.

[16]  Bruce J Aronow,et al.  Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[17]  D. Holtzman,et al.  In Vivo Assessment of Brain Interstitial Fluid with Microdialysis Reveals Plaque-Associated Changes in Amyloid-β Metabolism and Half-Life , 2003, The Journal of Neuroscience.

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

[19]  G. Bu,et al.  Genetics and molecular biology: phosphorylation of low-density lipoprotein receptor-related protein by platelet-derived growth factor , 2002, Current opinion in lipidology.

[20]  R. Deane,et al.  Early-onset and Robust Cerebral Microvascular Accumulation of Amyloid β-Protein in Transgenic Mice Expressing Low Levels of a Vasculotropic Dutch/Iowa Mutant Form of Amyloid β-Protein Precursor* , 2004, Journal of Biological Chemistry.

[21]  M. S. Brown,et al.  Proteolytic processing of the 600 kd low density lipoprotein receptor‐related protein (LRP) occurs in a trans‐Golgi compartment. , 1990, The EMBO journal.

[22]  R. Hammer,et al.  RAP, a specialized chaperone, prevents ligand‐induced ER retention and degradation of LDL receptor‐related endocytic receptors. , 1996, The EMBO journal.

[23]  J. Lambert,et al.  Association at LRP gene locus with sporadic late-onset Alzheimer's disease , 1998, The Lancet.

[24]  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.

[25]  B. Zlokovic,et al.  A simple method for isolation and characterization of mouse brain microvascular endothelial cells , 2003, Journal of Neuroscience Methods.

[26]  Mikio Shoji,et al.  Age-Dependent Changes in Brain, CSF, and Plasma Amyloid β Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease , 2001, The Journal of Neuroscience.

[27]  J. Thorell,et al.  Enzymatic iodination of polypeptides with 125I to high specific activity. , 1971, Biochimica et biophysica acta.

[28]  José A Fernández,et al.  Activated Protein C Prevents Neuronal Apoptosis via Protease Activated Receptors 1 and 3 , 2004, Neuron.

[29]  D. Holtzman,et al.  Clearance of amyloid β-peptide from brain: transport or metabolism? , 2000, Nature Medicine.

[30]  J. Ghiso,et al.  Amyloidosis and Alzheimer's disease. , 2002, Advanced drug delivery reviews.

[31]  B. Zlokovic,et al.  Human blood-brain barrier receptors for Alzheimer's amyloid-beta 1- 40. Asymmetrical binding, endocytosis, and transcytosis at the apical side of brain microvascular endothelial cell monolayer. , 1998, The Journal of clinical investigation.

[32]  K. Arai,et al.  Lipoprotein receptor–mediated induction of matrix metalloproteinase by tissue plasminogen activator , 2003, Nature Medicine.

[33]  J. Herz.  The LDL Receptor Gene Family (Un)Expected Signal Transducers in the Brain , 2001, Neuron.

[34]  Carl W. Cotman,et al.  Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis , 2003, Science.

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

[36]  D. Holtzman,et al.  Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. , 2000, The Journal of clinical investigation.

[37]  C. Cotman,et al.  Assembly and aggregation properties of synthetic Alzheimer's A4/beta amyloid peptide analogs. , 1992, The Journal of biological chemistry.

[38]  C. Finch,et al.  Alzheimer's disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[39]  C. Lemere,et al.  Novel Therapeutic Approach for the Treatment of Alzheimer's Disease by Peripheral Administration of Agents with an Affinity to β-Amyloid , 2003, The Journal of Neuroscience.

[40]  B. Hyman,et al.  Low‐density lipoprotein receptor‐related protein levels and endocytic function are reduced by overexpression of the FE65 adaptor protein, FE65L1 , 2002, Journal of neurochemistry.

[41]  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.

[42]  E. Matsubara,et al.  Glycoprotein 330/megalin: probable role in receptor-mediated transport of apolipoprotein J alone and in a complex with Alzheimer disease amyloid beta at the blood-brain and blood-cerebrospinal fluid barriers. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[43]  H. Geuze,et al.  Proteasome regulates the delivery of LDL receptor-related protein into the degradation pathway. , 2002, Molecular biology of the cell.

[44]  L. Thal,et al.  late-onset Alzheimer’s disease , 2007 .

[45]  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 .

[46]  H. Vinters,et al.  Amyloidosis of cerebral arteries. , 2003, Advances in neurology.

[47]  P. Lenting,et al.  The α-Chains of C4b-binding Protein Mediate Complex Formation with Low Density Lipoprotein Receptor-related Protein* , 2002, The Journal of Biological Chemistry.

[48]  Thomas Wisniewski,et al.  The Interaction between Apolipoprotein E and Alzheimers Amyloid -Peptide Is Dependent on -Peptide Conformation (*) , 1996, The Journal of Biological Chemistry.

[49]  E. Masliah,et al.  Role of Apolipoprotein E Receptors in Regulating the Differential in vivo Neurotrophic Effects of Apolipoprotein E , 2001, Experimental Neurology.

[50]  S. Greenberg,et al.  Pathogenic Effects of D23N Iowa Mutant Amyloid β-Protein* , 2001, The Journal of Biological Chemistry.

[51]  T. Grabowski,et al.  Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy , 2001, Annals of neurology.

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

[53]  D. Selkoe.  Clearing the Brain's Amyloid Cobwebs , 2001, Neuron.

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

[55]  M. Makuuchi,et al.  Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis , 2002, Nature Medicine.

[56]  P. Geer.  Phosphorylation of LRP1: Regulation of Transport and Signal Transduction , 2002 .

[57]  J. Herz,et al.  Coaxing the LDL Receptor Family into the Fold , 2003, Cell.

[58]  B. Hyman,et al.  Confirmation of an association between a polymorphism in exon 3 of the low‐density lipoprotein receptor‐related protein gene and Alzheimer's disease , 1998, Neurology.