β-arrestin 2 regulates Aβ generation and γ-secretase activity in Alzheimer's disease

β-arrestins are associated with numerous aspects of G protein–coupled receptor (GPCR) signaling and regulation and accordingly influence diverse physiological and pathophysiological processes. Here we report that β-arrestin 2 expression is elevated in two independent cohorts of individuals with Alzheimer's disease. Overexpression of β-arrestin 2 leads to an increase in amyloid-β (Aβ) peptide generation, whereas genetic silencing of Arrb2 (encoding β-arrestin 2) reduces generation of Aβ in cell cultures and in Arrb2−/− mice. Moreover, in a transgenic mouse model of Alzheimer's disease, genetic deletion of Arrb2 leads to a reduction in the production of Aβ40 and Aβ42. Two GPCRs implicated previously in Alzheimer's disease (GPR3 and the β2-adrenergic receptor) mediate their effects on Aβ generation through interaction with β-arrestin 2. β-arrestin 2 physically associates with the Aph-1a subunit of the γ-secretase complex and redistributes the complex toward detergent-resistant membranes, increasing the catalytic activity of the complex. Collectively, these studies identify β-arrestin 2 as a new therapeutic target for reducing amyloid pathology and GPCR dysfunction in Alzheimer's disease.

[1]  B. Strooper,et al.  Aph-1, Pen-2, and Nicastrin with Presenilin Generate an Active γ-Secretase Complex , 2003, Neuron.

[2]  Marc G. Caron,et al.  μ-Opioid receptor desensitization by β-arrestin-2 determines morphine tolerance but not dependence , 2000, Nature.

[3]  A. Ittner,et al.  Tau‐targeted treatment strategies in Alzheimer's disease , 2012, British journal of pharmacology.

[4]  J. Seidman,et al.  β-Arrestin1 Knockout Mice Appear Normal but Demonstrate Altered Cardiac Responses to β-Adrenergic Stimulation , 1997 .

[5]  Y. Ihara,et al.  Aβ46 Is Processed to Aβ40 and Aβ43, but Not to Aβ42, in the Low Density Membrane Domains* , 2008, Journal of Biological Chemistry.

[6]  Y. Shitaka,et al.  Differential Effects between γ-Secretase Inhibitors and Modulators on Cognitive Function in Amyloid Precursor Protein-Transgenic and Nontransgenic Mice , 2012, The Journal of Neuroscience.

[7]  Min Xu,et al.  Presenilin 1 is linked with γ-secretase activity in the detergent solubilized state , 2000, Neurobiology of Aging.

[8]  M. Parenti,et al.  G-protein coupled receptors in lipid rafts and caveolae: how, when and why do they go there? , 2004, Journal of molecular endocrinology.

[9]  R. Lefkowitz,et al.  Therapeutic potential of β-arrestin- and G protein-biased agonists. , 2011, Trends in molecular medicine.

[10]  Olivier Lichtarge,et al.  β-Arrestin-dependent, G Protein-independent ERK1/2 Activation by the β2 Adrenergic Receptor* , 2006, Journal of Biological Chemistry.

[11]  B. Strooper,et al.  The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics , 2011, Nature Reviews Drug Discovery.

[12]  M. Caron,et al.  Inhibition of beta-adrenergic receptor kinase prevents rapid homologous desensitization of beta 2-adrenergic receptors. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[13]  T. Gudermann,et al.  Receptors and G proteins as primary components of transmembrane signal transduction , 1995, Journal of Molecular Medicine.

[14]  S. Hébert,et al.  Coordinated and widespread expression of γ-secretase in vivo: evidence for size and molecular heterogeneity , 2004, Neurobiology of Disease.

[15]  R. Gainetdinov,et al.  Enhanced morphine analgesia in mice lacking beta-arrestin 2. , 1999, Science.

[16]  B. de Strooper,et al.  Presenilin 1 mediates the turnover of telencephalin in hippocampal neurons via an autophagic degradative pathway , 2004, The Journal of cell biology.

[17]  Jiuhong Kang,et al.  Deficiency of a β-arrestin-2 signal complex contributes to insulin resistance , 2009, Nature.

[18]  R. Tanzi,et al.  The Genetics of Alzheimer Disease: Back to the Future , 2010, Neuron.

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

[20]  D. Scheinberg,et al.  Familial Alzheimer Disease Presenilin-1 Mutations Alter the Active Site Conformation of γ-secretase* , 2012, The Journal of Biological Chemistry.

[21]  D. Selkoe,et al.  Resolving controversies on the path to Alzheimer's therapeutics , 2011, Nature Medicine.

[22]  D. Holtzman,et al.  Mapping the Road Forward in Alzheimer’s Disease , 2011, Science Translational Medicine.

[23]  Gang Pei,et al.  A GPCR/secretase complex regulates β- and γ-secretase specificity for Aβ production and contributes to AD pathogenesis , 2010, Cell Research.

[24]  B. Strooper,et al.  The role of G protein-coupled receptors in the pathology of Alzheimer's disease , 2011, Nature Reviews Neuroscience.

[25]  D. Selkoe,et al.  Activity-dependent isolation of the presenilin– γ-secretase complex reveals nicastrin and a γ substrate , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Hartwig Wolburg,et al.  Aβ42‐driven cerebral amyloidosis in transgenic mice reveals early and robust pathology , 2006, EMBO reports.

[27]  Min Xu,et al.  Presenilin 1 is linked with gamma-secretase activity in the detergent solubilized state. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[28]  L. Hunyady,et al.  The role of a conserved region of the second intracellular loop in AT1 angiotensin receptor activation and signaling. , 2003, Endocrinology.

[29]  A. Fagan,et al.  APOE predicts amyloid‐beta but not tau Alzheimer pathology in cognitively normal aging , 2010, Annals of neurology.

[30]  B. Strooper,et al.  Interaction with Telencephalin and the Amyloid Precursor Protein Predicts a Ring Structure for Presenilins , 2001, Neuron.

[31]  J. Wess,et al.  The M3-muscarinic receptor regulates learning and memory in a receptor phosphorylation/arrestin-dependent manner , 2010, Proceedings of the National Academy of Sciences.

[32]  Todd E. Golde,et al.  Anti-Aβ Therapeutics in Alzheimer's Disease: The Need for a Paradigm Shift , 2011, Neuron.

[33]  William J. Ray,et al.  A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain , 1999, Nature.

[34]  H. Braak,et al.  Neuropathological stageing of Alzheimer-related changes , 2004, Acta Neuropathologica.

[35]  R. Lefkowitz,et al.  Differential Kinetic and Spatial Patterns of β-Arrestin and G Protein-mediated ERK Activation by the Angiotensin II Receptor* , 2004, Journal of Biological Chemistry.

[36]  T. Sotnikova,et al.  An Akt/β-Arrestin 2/PP2A Signaling Complex Mediates Dopaminergic Neurotransmission and Behavior , 2005, Cell.

[37]  T. Gudermann,et al.  Receptors and G proteins as primary components of transmembrane signal transduction , 1995, Journal of Molecular Medicine.

[38]  M. Caron,et al.  Role of β-Arrestin in Mediating Agonist-Promoted G Protein-Coupled Receptor Internalization , 1996, Science.

[39]  D. Selkoe,et al.  Detergent-dependent dissociation of active gamma-secretase reveals an interaction between Pen-2 and PS1-NTF and offers a model for subunit organization within the complex. , 2004, Biochemistry.

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

[41]  Hugo Vanderstichele,et al.  Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein , 1998, Nature.

[42]  B. De Strooper,et al.  The Orphan G Protein–Coupled Receptor 3 Modulates Amyloid-Beta Peptide Generation in Neurons , 2009, Science.

[43]  H. Schiöth,et al.  The Repertoire of G-Protein–Coupled Receptors in Fully Sequenced Genomes , 2005, Molecular Pharmacology.

[44]  S. Younkin,et al.  Cholesterol-Dependent γ-Secretase Activity in Buoyant Cholesterol-Rich Membrane Microdomains , 2002, Neurobiology of Disease.

[45]  R. Lefkowitz,et al.  β-Arrestins and Cell Signaling , 2007 .

[46]  L. Hunyady,et al.  Independent β-arrestin 2 and G protein-mediated pathways for angiotensin II activation of extracellular signal-regulated kinases 1 and 2 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[47]  J. Trojanowski,et al.  Tau-mediated neurodegeneration in Alzheimer's disease and related disorders , 2007, Nature Reviews Neuroscience.

[48]  S V Faraone,et al.  Genetics of Alzheimer's disease. , 1996, Journal of the Formosan Medical Association = Taiwan yi zhi.

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

[50]  R. Rodriguiz,et al.  A β-arrestin 2 Signaling Complex Mediates Lithium Action on Behavior , 2008, Cell.

[51]  H. Cai,et al.  BACE1 is the major β-secretase for generation of Aβ peptides by neurons , 2001, Nature Neuroscience.

[52]  角田 聡子.  γ-secretase activity is present in rafts but is not cholesterol-dependent , 2006 .

[53]  Donald A. Wilson,et al.  ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models , 2012, Science.

[54]  C. Kruse,et al.  Concerted changes in transcripts in the prefrontal cortex precede neuropathology in Alzheimer's disease. , 2010, Brain : a journal of neurology.

[55]  Graeme Irvine Stevenson,et al.  L-685,458, an Aspartyl Protease Transition State Mimic, Is a Potent Inhibitor of Amyloid β-Protein Precursor γ-Secretase Activity , 2000 .

[56]  M. Caron,et al.  Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes. , 1999, Science.

[57]  M. Mortrud,et al.  The G protein-coupled receptor repertoires of human and mouse , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[58]  R. Eglen,et al.  Beta galactosidase complementation: a cell-based luminescent assay platform for drug discovery. , 2007, Assay and drug development technologies.

[59]  L. Tarassishin,et al.  Stereoselective Synthesis of Photoreactive Peptidomimetic γ-Secretase Inhibitors , 2004 .