Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Expert Review
  • Published:

Alzheimer disease: modeling an Aβ-centered biological network

Molecular Psychiatry volume 21, pages 861–871 (2016)Cite this article

Subjects

Abstract

In genetically complex diseases, the search for missing heritability is focusing on rare variants with large effect. Thanks to next generation sequencing technologies, genome-wide characterization of these variants is now feasible in every individual. However, a lesson from current studies is that collapsing rare variants at the gene level is often insufficient to obtain a statistically significant signal in case–control studies, and that network-based analyses are an attractive complement to classical approaches. In Alzheimer disease (AD), according to the prevalent amyloid cascade hypothesis, the pathology is driven by the amyloid beta (Aβ) peptide. In past years, based on experimental studies, several hundreds of proteins have been shown to interfere with Aβ production, clearance, aggregation or toxicity. Thanks to a manual curation of the literature, we identified 335 genes/proteins involved in this biological network and classified them according to their cellular function. The complete list of genes, or its subcomponents, will be of interest in ongoing AD genetic studies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Rosso SM, Kamphorst W, Ravid R, van Swieten JC . Coexistent tau and amyloid pathology in hereditary frontotemporal dementia with tau mutations. Ann NY Acad Sci 2000; 920: 115–119.

    Article  CAS  PubMed  Google Scholar 

  2. Ishida C, Kobayashi K, Kitamura T, Ujike H, Iwasa K, Yamada M . Frontotemporal dementia with parkinsonism linked to chromosome 17 with the MAPT R406W mutation presenting with a broad distribution of abundant senile plaques. Neuropathology 2015; 35: 75–82.

    Article  CAS  PubMed  Google Scholar 

  3. Hurtado DE, Molina-Porcel L, Iba M, Aboagye AK, Paul SM, Trojanowski JQ et al. A{beta} accelerates the spatiotemporal progression of tau pathology and augments tau amyloidosis in an Alzheimer mouse model. Am J Pathol 2010; 177: 1977–1988.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hardy JA, Higgins GA . Alzheimer's disease: the amyloid cascade hypothesis. Science 1992; 256: 184–185.

    Article  CAS  PubMed  Google Scholar 

  5. Walsh DM, Selkoe DJ . A beta oligomers—a decade of discovery. J Neurochem 2007; 101: 1172–1184.

    Article  CAS  PubMed  Google Scholar 

  6. Braak H, Braak E . Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991; 82: 239–259.

    Article  CAS  PubMed  Google Scholar 

  7. Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT . Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology 1992; 42: 631–639.

    Article  CAS  PubMed  Google Scholar 

  8. Delacourte A, Sergeant N, Champain D, Wattez A, Maurage CA, Lebert F et al. Nonoverlapping but synergetic tau and APP pathologies in sporadic Alzheimer's disease. Neurology 2002; 59: 398–407.

    Article  CAS  PubMed  Google Scholar 

  9. Ittner LM, Gotz J . Amyloid-beta and tau—a toxic pas de deux in Alzheimer's disease. Nat Rev Neurosci 2011; 12: 65–72.

    Article  CAS  PubMed  Google Scholar 

  10. Bloom GS . Amyloid-beta and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol 2014; 71: 505–508.

    Article  PubMed  Google Scholar 

  11. Duyckaerts C . Neurodegenerative lesions: seeding and spreading. Rev Neurol 2013; 169: 825–833.

    Article  CAS  PubMed  Google Scholar 

  12. Musiek ES, Holtzman DM . Three dimensions of the amyloid hypothesis: time, space and 'wingmen'. Nat Neurosci 2015; 18: 800–806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Genin E, Hannequin D, Wallon D, Sleegers K, Hiltunen M, Combarros O et al. APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol Psychiatry 2011; 16: 903–907.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet 2013; 45: 1452–1458.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J et al. Variant of TREM2 associated with the risk of Alzheimer's disease. New Engl J Med 2013; 368: 107–116.

    Article  CAS  PubMed  Google Scholar 

  16. Wu G, Zhi D . Pathway-based approaches for sequencing-based genome-wide association studies. Genet Epidemiol 2013; 37: 478–494.

    Article  PubMed  Google Scholar 

  17. Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F et al. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 2007; 39: 168–177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Iossifov I, O'Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature 2014; 515: 216–221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Rovelet-Lecrux A, Charbonnier C, Wallon D, Nicolas G, Seaman MN, Pottier C et al. De novo deleterious genetic variations target a biological network centered on Abeta peptide in early-onset Alzheimer disease. Mol Psychiatry 2015; 20: 1046–1056.

    Article  CAS  PubMed  Google Scholar 

  20. Haass C, Kaether C, Thinakaran G, Sisodia S . Trafficking and proteolytic processing of APP. Cold Spring Harb Perspect Med 2012; 2: a006270.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Claeysen S, Cochet M, Donneger R, Dumuis A, Bockaert J, Giannoni P . Alzheimer culprits: cellular crossroads and interplay. Cell Signal 2012; 24: 1831–1840.

    Article  CAS  PubMed  Google Scholar 

  22. De Strooper B . Proteases and proteolysis in Alzheimer disease: a multifactorial view on the disease process. Physiol Rev 2010; 90: 465–494.

    Article  CAS  PubMed  Google Scholar 

  23. Hoshino T, Nakaya T, Araki W, Suzuki K, Suzuki T, Mizushima T . Endoplasmic reticulum chaperones inhibit the production of amyloid-beta peptides. Biochem J 2007; 402: 581–589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Huttunen HJ, Guenette SY, Peach C, Greco C, Xia W, Kim DY et al. HtrA2 regulates beta-amyloid precursor protein (APP) metabolism through endoplasmic reticulum-associated degradation. J Biol Chem 2007; 282: 28285–28295.

    Article  CAS  PubMed  Google Scholar 

  25. Kaneko M, Koike H, Saito R, Kitamura Y, Okuma Y, Nomura Y . Loss of HRD1-mediated protein degradation causes amyloid precursor protein accumulation and amyloid-beta generation. J Neurosci 2010; 30: 3924–3932.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kumar P, Ambasta RK, Veereshwarayya V, Rosen KM, Kosik KS, Band H et al. CHIP and HSPs interact with beta-APP in a proteasome-dependent manner and influence Abeta metabolism. Hum Mol Genet 2007; 16: 848–864.

    Article  CAS  PubMed  Google Scholar 

  27. Ullrich S, Munch A, Neumann S, Kremmer E, Tatzelt J, Lichtenthaler SF . The novel membrane protein TMEM59 modulates complex glycosylation, cell surface expression, and secretion of the amyloid precursor protein. J Biol Chem 2010; 285: 20664–20674.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Parisiadou L, Bethani I, Michaki V, Krousti K, Rapti G, Efthimiopoulos S . Homer2 and Homer3 interact with amyloid precursor protein and inhibit Abeta production. Neurobiol Dis 2008; 30: 353–364.

    Article  CAS  PubMed  Google Scholar 

  29. Zhou X, Hu X, He W, Tang X, Shi Q, Zhang Z et al. Interaction between amyloid precursor protein and Nogo receptors regulates amyloid deposition. FASEB J 2011; 25: 3146–3156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang J, Shan C, Cao W, Zhang C, Teng J, Chen J . SCG10 promotes non-amyloidogenic processing of amyloid precursor protein by facilitating its trafficking to the cell surface. Hum Mol Genet 2013; 22: 4888–4900.

    Article  CAS  PubMed  Google Scholar 

  31. Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL et al. Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease. Science 2005; 307: 1282–1288.

    Article  CAS  PubMed  Google Scholar 

  32. Steuble M, Diep TM, Schatzle P, Ludwig A, Tagaya M, Kunz B et al. Calsyntenin-1 shelters APP from proteolytic processing during anterograde axonal transport. Biol Open 2012; 1: 761–774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yang GZ, Yang M, Lim Y, Lu JJ, Wang TH, Qi JG et al. Huntingtin associated protein 1 regulates trafficking of the amyloid precursor protein and modulates amyloid beta levels in neurons. J Neurochem 2012; 122: 1010–1022.

    Article  CAS  PubMed  Google Scholar 

  34. Sisodia SS . Beta-amyloid precursor protein cleavage by a membrane-bound protease. Proc Natl Acad Sci USA 1992; 89: 6075–6079.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kuhn PH, Wang H, Dislich B, Colombo A, Zeitschel U, Ellwart JW et al. ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J 2010; 29: 3020–3032.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Suh J, Choi SH, Romano DM, Gannon MA, Lesinski AN, Kim DY et al. ADAM10 missense mutations potentiate beta-amyloid accumulation by impairing prodomain chaperone function. Neuron 2013; 80: 385–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Donmez G, Wang D, Cohen DE, Guarente L . SIRT1 suppresses beta-amyloid production by activating the alpha-secretase gene ADAM10. Cell 2010; 142: 320–332.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Xu D, Sharma C, Hemler ME . Tetraspanin12 regulates ADAM10-dependent cleavage of amyloid precursor protein. FASEB J 2009; 23: 3674–3681.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ohno M, Hiraoka Y, Lichtenthaler SF, Nishi K, Saijo S, Matsuoka T et al. Nardilysin prevents amyloid plaque formation by enhancing alpha-secretase activity in an Alzheimer's disease mouse model. Neurobiol Aging 2014; 35: 213–222.

    Article  CAS  PubMed  Google Scholar 

  40. Marcello E, Gardoni F, Mauceri D, Romorini S, Jeromin A, Epis R et al. Synapse-associated protein-97 mediates alpha-secretase ADAM10 trafficking and promotes its activity. J Neurosci 2007; 27: 1682–1691.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Amour A, Knight CG, Webster A, Slocombe PM, Stephens PE, Knauper V et al. The in vitro activity of ADAM-10 is inhibited by TIMP-1 and TIMP-3. FEBS Lett 2000; 473: 275–279.

    Article  CAS  PubMed  Google Scholar 

  42. Vingtdeux V, Marambaud P . Identification and biology of alpha-secretase. J Neurochem 2012; 120: 34–45.

    Article  CAS  PubMed  Google Scholar 

  43. Capell A, Steiner H, Willem M, Kaiser H, Meyer C, Walter J et al. Maturation and pro-peptide cleavage of beta-secretase. J Biol Chem 2000; 275: 30849–30854.

    Article  CAS  PubMed  Google Scholar 

  44. He W, Lu Y, Qahwash I, Hu XY, Chang A, Yan R . Reticulon family members modulate BACE1 activity and amyloid-beta peptide generation. Nat Med 2004; 10: 959–965.

    Article  CAS  PubMed  Google Scholar 

  45. Ho A, Sudhof TC . Binding of F-spondin to amyloid-beta precursor protein: a candidate amyloid-beta precursor protein ligand that modulates amyloid-beta precursor protein cleavage. Proc Natl Acad Sci USA 2004; 101: 2548–2553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Matsuda S, Giliberto L, Matsuda Y, McGowan EM, D'Adamio L . BRI2 inhibits amyloid beta-peptide precursor protein processing by interfering with the docking of secretases to the substrate. J Neurosci 2008; 28: 8668–8676.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Matsuda S, Matsuda Y, D'Adamio L . BRI3 inhibits amyloid precursor protein processing in a mechanistically distinct manner from its homologue dementia gene BRI2. J Biol Chem 2009; 284: 15815–15825.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Udayar V, Buggia-Prevot V, Guerreiro RL, Siegel G, Rambabu N, Soohoo AL et al. A paired RNAi and RabGAP overexpression screen identifies Rab11 as a regulator of beta-amyloid production. Cell Rep 2013; 5: 1536–1551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sannerud R, Declerck I, Peric A, Raemaekers T, Menendez G, Zhou L et al. ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1. Proc Natl Acad Sci USA 2011; 108: E559–E568.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Buggia-Prevot V, Fernandez CG, Udayar V, Vetrivel KS, Elie A, Roseman J et al. A function for EHD family proteins in unidirectional retrograde dendritic transport of BACE1 and Alzheimer's disease Abeta production. Cell Rep 2013; 5: 1552–1563.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Wahle T, Thal DR, Sastre M, Rentmeister A, Bogdanovic N, Famulok M et al. GGA1 is expressed in the human brain and affects the generation of amyloid beta-peptide. J Neurosci 2006; 26: 12838–12846.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sarajarvi T, Haapasalo A, Viswanathan J, Makinen P, Laitinen M, Soininen H et al. Down-regulation of seladin-1 increases BACE1 levels and activity through enhanced GGA3 depletion during apoptosis. J Biol Chem 2009; 284: 34433–34443.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Tesco G, Koh YH, Kang EL, Cameron AN, Das S, Sena-Esteves M et al. Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity. Neuron 2007; 54: 721–737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zhang M, Deng Y, Luo Y, Zhang S, Zou H, Cai F et al. Control of BACE1 degradation and APP processing by ubiquitin carboxyl-terminal hydrolase L1. J Neurochem 2012; 120: 1129–1138.

    CAS  PubMed  Google Scholar 

  55. Gray EH, De Vos KJ, Dingwall C, Perkinton MS, Miller CC . Deficiency of the copper chaperone for superoxide dismutase increases amyloid-beta production. JAD 2010; 21: 1101–1105.

    Article  CAS  PubMed  Google Scholar 

  56. Li Y, Bohm C, Dodd R, Chen F, Qamar S, Schmitt-Ulms G et al. Structural biology of presenilin 1 complexes. Mol Neurodegener 2014; 9: 59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wang X, Huang T, Zhao Y, Zheng Q, Thompson RC, Bu G et al. Sorting nexin 27 regulates Abeta production through modulating gamma-secretase activity. Cell Rep 2014; 9: 1023–1033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Cai D, Netzer WJ, Zhong M, Lin Y, Du G, Frohman M et al. Presenilin-1 uses phospholipase D1 as a negative regulator of beta-amyloid formation. Proc Natl Acad Sci USA 2006; 103: 1941–1946.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Park HJ, Shabashvili D, Nekorchuk MD, Shyqyriu E, Jung JI, Ladd TB et al. Retention in endoplasmic reticulum 1 (RER1) modulates amyloid-beta (Abeta) production by altering trafficking of gamma-secretase and amyloid precursor protein (APP). J Biol Chem 2012; 287: 40629–40640.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Tanabe C, Maeda T, Zou K, Liu J, Liu S, Nakajima T et al. The ubiquitin ligase synoviolin up-regulates amyloid beta production by targeting a negative regulator of gamma-secretase, Rer1, for degradation. J Biol Chem 2012; 287: 44203–44211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Mitsuishi Y, Hasegawa H, Matsuo A, Araki W, Suzuki T, Tagami S et al. Human CRB2 inhibits gamma-secretase cleavage of amyloid precursor protein by binding to the presenilin complex. J Biol Chem 2010; 285: 14920–14931.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Pardossi-Piquard R, Bohm C, Chen F, Kanemoto S, Checler F, Schmitt-Ulms G et al. TMP21 transmembrane domain regulates gamma-secretase cleavage. J Biol Chem 2009; 284: 28634–28641.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. He G, Luo W, Li P, Remmers C, Netzer WJ, Hendrick J et al. Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease. Nature 2010; 467: 95–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhou S, Zhou H, Walian PJ, Jap BK . CD147 is a regulatory subunit of the gamma-secretase complex in Alzheimer's disease amyloid beta-peptide production. Proc Natl Acad Sci USA 2005; 102: 7499–7504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wu J, Petralia RS, Kurushima H, Patel H, Jung MY, Volk L et al. Arc/Arg3.1 regulates an endosomal pathway essential for activity-dependent beta-amyloid generation. Cell 2011; 147: 615–628.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Thathiah A, Horre K, Snellinx A, Vandewyer E, Huang Y, Ciesielska M et al. Beta-arrestin 2 regulates Abeta generation and gamma-secretase activity in Alzheimer's disease. Nat Med 2013; 19: 43–49.

    Article  CAS  PubMed  Google Scholar 

  67. Vetrivel KS, Thinakaran G . Membrane rafts in Alzheimer's disease beta-amyloid production. Biochim Biophys Acta 2010; 1801: 860–867.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Wollmer MA . Cholesterol-related genes in Alzheimer's disease. Biochim Biophys Acta 2010; 1801: 762–773.

    Article  CAS  PubMed  Google Scholar 

  69. Michaki V, Guix FX, Vennekens K, Munck S, Dingwall C, Davis JB et al. Down-regulation of the ATP-binding cassette transporter 2 (Abca2) reduces amyloid-beta production by altering nicastrin maturation and intracellular localization. J Biol Chem 2012; 287: 1100–1111.

    Article  CAS  PubMed  Google Scholar 

  70. Cirrito JR, Kang JE, Lee J, Stewart FR, Verges DK, Silverio LM et al. Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron 2008; 58: 42–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Cheng H, Vetrivel KS, Gong P, Meckler X, Parent A, Thinakaran G . Mechanisms of disease: new therapeutic strategies for Alzheimer's disease—targeting APP processing in lipid rafts. Nat Clin Pract Neurol 2007; 3: 374–382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. King GD, Scott Turner R . Adaptor protein interactions: modulators of amyloid precursor protein metabolism and Alzheimer's disease risk? Exp Neurol 2004; 185: 208–219.

    Article  CAS  PubMed  Google Scholar 

  73. Shahani N, Seshadri S, Jaaro-Peled H, Ishizuka K, Hirota-Tsuyada Y, Wang Q et al. DISC1 regulates trafficking and processing of APP and Abeta generation. Mol Psychiatry 2015; 20: 874–879.

    Article  CAS  PubMed  Google Scholar 

  74. Xiao Q, Gil SC, Yan P, Wang Y, Han S, Gonzales E et al. Role of phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) in intracellular amyloid precursor protein (APP) processing and amyloid plaque pathogenesis. J Biol Chem 2012; 287: 21279–21289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Carey RM, Balcz BA, Lopez-Coviella I, Slack BE . Inhibition of dynamin-dependent endocytosis increases shedding of the amyloid precursor protein ectodomain and reduces generation of amyloid beta protein. BMC Cell Biol 2005; 6: 30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Schobel S, Neumann S, Hertweck M, Dislich B, Kuhn PH, Kremmer E et al. A novel sorting nexin modulates endocytic trafficking and alpha-secretase cleavage of the amyloid precursor protein. J Biol Chem 2008; 283: 14257–14268.

    Article  CAS  PubMed  Google Scholar 

  77. Small SA, Gandy S . Sorting through the cell biology of Alzheimer's disease: intracellular pathways to pathogenesis. Neuron 2006; 52: 15–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Reitz C . The role of the retromer complex in aging-related neurodegeneration: a molecular and genomic review. Mol Genet Genomics 2015; 290: 413–427.

    Article  CAS  PubMed  Google Scholar 

  79. Muhammad A, Flores I, Zhang H, Yu R, Staniszewski A, Planel E et al. Retromer deficiency observed in Alzheimer's disease causes hippocampal dysfunction, neurodegeneration, and Abeta accumulation. Proc Natl Acad Sci USA 2008; 105: 7327–7332.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Pottier C, Hannequin D, Coutant S, Rovelet-Lecrux A, Wallon D, Rousseau S et al. High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Mol Psychiatry 2012; 17: 875–879.

    Article  CAS  PubMed  Google Scholar 

  81. Nicolas G, Charbonnier C, Wallon D, Quenez O, Bellenguez C, Grenier-Boley B et al. SORL1 rare variants: a major risk factor for familial early-onset Alzheimer's disease. Mol Psychiatry 2015. doi: 10.1038/mp.2015.121.

  82. DeMattos RB, Cirrito JR, Parsadanian M, May PC, O'Dell MA, Taylor JW et al. ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular Abeta metabolism in vivo. Neuron 2004; 41: 193–202.

    Article  CAS  PubMed  Google Scholar 

  83. Bettens K, Brouwers N, Engelborghs S, Lambert JC, Rogaeva E, Vandenberghe R et al. Both common variations and rare non-synonymous substitutions and small insertion/deletions in CLU are associated with increased Alzheimer risk. Mol Neurodegener 2012; 7: 3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Liu CC, Kanekiyo T, Xu H, Bu G . Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 2013; 9: 106–118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Koldamova R, Fitz NF, Lefterov I . The role of ATP-binding cassette transporter A1 in Alzheimer's disease and neurodegeneration. Biochim Biophys Acta 2010; 1801: 824–830.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Deane R, Bell RD, Sagare A, Zlokovic BV . Clearance of amyloid-beta peptide across the blood-brain barrier: implication for therapies in Alzheimer's disease. CNS Neurol Disord Drug Targets 2009; 8: 16–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Bell RD, Sagare AP, Friedman AE, Bedi GS, Holtzman DM, Deane R et al. Transport pathways for clearance of human Alzheimer's amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. J Cereb Blood Flow Metab 2007; 27: 909–918.

    Article  CAS  PubMed  Google Scholar 

  88. Kanekiyo T, Cirrito JR, Liu CC, Shinohara M, Li J, Schuler DR et al. Neuronal clearance of amyloid-beta by endocytic receptor LRP1. J Neurosci 2013; 33: 19276–19283.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Iwata N, Tsubuki S, Takaki Y, Shirotani K, Lu B, Gerard NP et al. Metabolic regulation of brain Abeta by neprilysin. Science 2001; 292: 1550–1552.

    Article  CAS  PubMed  Google Scholar 

  90. Qiu WQ, Walsh DM, Ye Z, Vekrellis K, Zhang J, Podlisny MB et al. Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. J Biol Chem 1998; 273: 32730–32738.

    Article  CAS  PubMed  Google Scholar 

  91. Liao MC, Van Nostrand WE . Degradation of soluble and fibrillar amyloid beta-protein by matrix metalloproteinase (MT1-MMP) in vitro. Biochemistry 2010; 49: 1127–1136.

    Article  CAS  PubMed  Google Scholar 

  92. Backstrom JR, Lim GP, Cullen MJ, Tokes ZA . Matrix metalloproteinase-9 (MMP-9) is synthesized in neurons of the human hippocampus and is capable of degrading the amyloid-beta peptide (1-40). J Neurosci 1996; 16: 7910–7919.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Zou K, Yamaguchi H, Akatsu H, Sakamoto T, Ko M, Mizoguchi K et al. Angiotensin-converting enzyme converts amyloid beta-protein 1-42 (Abeta(1-42)) to Abeta(1-40), and its inhibition enhances brain Abeta deposition. J Neurosci 2007; 27: 8628–8635.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Pacheco-Quinto J, Eckman EA . Endothelin-converting enzymes degrade intracellular beta-amyloid produced within the endosomal/lysosomal pathway and autophagosomes. J Biol Chem 2013; 288: 5606–5615.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kim MJ, Chae SS, Koh YH, Lee SK, Jo SA . Glutamate carboxypeptidase II: an amyloid peptide-degrading enzyme with physiological function in the brain. FASEB J 2010; 24: 4491–4502.

    Article  CAS  PubMed  Google Scholar 

  96. Abdul-Hay SO, Sahara T, McBride M, Kang D, Leissring MA . Identification of BACE2 as an avid ss-amyloid-degrading protease. Mol Neurodegener 2012; 7: 46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Mueller-Steiner S, Zhou Y, Arai H, Roberson ED, Sun B, Chen J et al. Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer's disease. Neuron 2006; 51: 703–714.

    Article  CAS  PubMed  Google Scholar 

  98. Lee CY, Landreth GE . The role of microglia in amyloid clearance from the AD brain. J Neural Transm 2010; 117: 949–960.

    Article  CAS  PubMed  Google Scholar 

  99. Salminen A, Ojala J, Kauppinen A, Kaarniranta K, Suuronen T . Inflammation in Alzheimer's disease: amyloid-beta oligomers trigger innate immunity defence via pattern recognition receptors. Prog Neurobiol 2009; 87: 181–194.

    Article  CAS  PubMed  Google Scholar 

  100. Heneka MT, Golenbock DT, Latz E . Innate immunity in Alzheimer's disease. Nat Immunol 2015; 16: 229–236.

    Article  CAS  PubMed  Google Scholar 

  101. Maier M, Peng Y, Jiang L, Seabrook TJ, Carroll MC, Lemere CA . Complement C3 deficiency leads to accelerated amyloid beta plaque deposition and neurodegeneration and modulation of the microglia/macrophage phenotype in amyloid precursor protein transgenic mice. J Neurosci 2008; 28: 6333–6341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Crehan H, Holton P, Wray S, Pocock J, Guerreiro R, Hardy J . Complement receptor 1 (CR1) and Alzheimer's disease. Immunobiology 2012; 217: 244–250.

    Article  CAS  PubMed  Google Scholar 

  103. Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL et al. Neuroinflammation in Alzheimer's disease. Lancet Neurol 2015; 14: 388–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL, Robinette ML et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell 2015; 160: 1061–1071.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D et al. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 2006; 442: 920–924.

    Article  CAS  PubMed  Google Scholar 

  106. Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 2006; 442: 916–919.

    Article  CAS  PubMed  Google Scholar 

  107. Perry DC, Lehmann M, Yokoyama JS, Karydas A, Lee JJ, Coppola G et al. Progranulin mutations as risk factors for Alzheimer disease. JAMA Neurol 2013; 70: 774–778.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Minami SS, Min SW, Krabbe G, Wang C, Zhou Y, Asgarov R et al. Progranulin protects against amyloid beta deposition and toxicity in Alzheimer's disease mouse models. Nat Med 2014; 20: 1157–1164.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Steinberg S, Stefansson H, Jonsson T, Johannsdottir H, Ingason A, Helgason H et al. Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease. Nat Genet 2015; 47: 445–447.

    Article  CAS  PubMed  Google Scholar 

  110. Zhao QF, Yu JT, Tan MS, Tan L . ABCA7 in Alzheimer's disease. Mol Neurobiol 2015; 51: 1008–1016.

    Article  CAS  PubMed  Google Scholar 

  111. Satoh K, Abe-Dohmae S, Yokoyama S St, George-Hyslop P, Fraser PE . ABCA7 loss of function alters Alzheimer amyloid processing. J Biol Chem 2015; 290: 24152–24165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Gregori L, Fuchs C, Figueiredo-Pereira ME, Van Nostrand WE, Goldgaber D . Amyloid beta-protein inhibits ubiquitin-dependent protein degradation in vitro. J Biol Chem 1995; 270: 19702–19708.

    Article  CAS  PubMed  Google Scholar 

  113. Burns MP, Zhang L, Rebeck GW, Querfurth HW, Moussa CE . Parkin promotes intracellular Abeta1-42 clearance. Hum Mol Genet 2009; 18: 3206–3216.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A et al. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol 2005; 64: 113–122.

    Article  PubMed  Google Scholar 

  115. Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger PA et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest 2008; 118: 2190–2199.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Benilova I, Karran E, De Strooper B . The toxic Abeta oligomer and Alzheimer's disease: an emperor in need of clothes. Nat Neurosci 2012; 15: 349–357.

    Article  CAS  PubMed  Google Scholar 

  117. Hartley DM, Zhao C, Speier AC, Woodard GA, Li S, Li Z et al. Transglutaminase induces protofibril-like amyloid beta-protein assemblies that are protease-resistant and inhibit long-term potentiation. J Biol Chem 2008; 283: 16790–16800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Schlenzig D, Ronicke R, Cynis H, Ludwig HH, Scheel E, Reymann K et al. N-terminal pyroglutamate formation of Abeta38 and Abeta40 enforces oligomer formation and potency to disrupt hippocampal long-term potentiation. J Neurochem 2012; 121: 774–784.

    Article  CAS  PubMed  Google Scholar 

  119. Kumar S, Rezaei-Ghaleh N, Terwel D, Thal DR, Richard M, Hoch M et al. Extracellular phosphorylation of the amyloid beta-peptide promotes formation of toxic aggregates during the pathogenesis of Alzheimer's disease. EMBO J 2011; 30: 2255–2265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Lee JY, Cole TB, Palmiter RD, Suh SW, Koh JY . Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice. Proc Natl Acad Sci USA 2002; 99: 7705–7710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Evans CG, Wisen S, Gestwicki JE . Heat shock proteins 70 and 90 inhibit early stages of amyloid beta-(1-42) aggregation in vitro. J Biol Chem 2006; 281: 33182–33191.

    Article  CAS  PubMed  Google Scholar 

  122. Ojha J, Masilamoni G, Dunlap D, Udoff RA, Cashikar AG . Sequestration of toxic oligomers by HspB1 as a cytoprotective mechanism. Mol Cell Biol 2011; 31: 3146–3157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Wilhelmus MM, Boelens WC, Otte-Holler I, Kamps B, de Waal RM, Verbeek MM . Small heat shock proteins inhibit amyloid-beta protein aggregation and cerebrovascular amyloid-beta protein toxicity. Brain Res 2006; 1089: 67–78.

    Article  CAS  PubMed  Google Scholar 

  124. Inestrosa NC, Alvarez A, Perez CA, Moreno RD, Vicente M, Linker C et al. Acetylcholinesterase accelerates assembly of amyloid-beta-peptides into Alzheimer's fibrils: possible role of the peripheral site of the enzyme. Neuron 1996; 16: 881–891.

    Article  CAS  PubMed  Google Scholar 

  125. Holtzman DM, Bales KR, Tenkova T, Fagan AM, Parsadanian M, Sartorius LJ et al. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. Proc Natl Acad Sci USA 2000; 97: 2892–2897.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Cotman SL, Halfter W, Cole GJ . Agrin binds to beta-amyloid (Abeta), accelerates abeta fibril formation, and is localized to Abeta deposits in Alzheimer's disease brain. Mol Cell Neurosci 2000; 15: 183–198.

    Article  CAS  PubMed  Google Scholar 

  127. Castillo GM, Ngo C, Cummings J, Wight TN, Snow AD . Perlecan binds to the beta-amyloid proteins (A beta) of Alzheimer's disease, accelerates A beta fibril formation, and maintains A beta fibril stability. J Neurochem 1997; 69: 2452–2465.

    Article  CAS  PubMed  Google Scholar 

  128. Diamant S, Podoly E, Friedler A, Ligumsky H, Livnah O, Soreq H . Butyrylcholinesterase attenuates amyloid fibril formation in vitro. Proc Natl Acad Sci USA 2006; 103: 8628–8633.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Li X, Zhang X, Ladiwala AR, Du D, Yadav JK, Tessier PM et al. Mechanisms of transthyretin inhibition of beta-amyloid aggregation in vitro. J Neurosci 2013; 33: 19423–19433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Nuutinen T, Suuronen T, Kauppinen A, Salminen A . Clusterin: a forgotten player in Alzheimer's disease. Brain Res Rev 2009; 61: 89–104.

    Article  CAS  PubMed  Google Scholar 

  131. Hughes SR, Khorkova O, Goyal S, Knaeblein J, Heroux J, Riedel NG et al. Alpha2-macroglobulin associates with beta-amyloid peptide and prevents fibril formation. Proc Natl Acad Sci USA 1998; 95: 3275–3280.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Kaeser SA, Herzig MC, Coomaraswamy J, Kilger E, Selenica ML, Winkler DT et al. Cystatin C modulates cerebral beta-amyloidosis. Nat Genet 2007; 39: 1437–1439.

    Article  CAS  PubMed  Google Scholar 

  133. Mi W, Pawlik M, Sastre M, Jung SS, Radvinsky DS, Klein AM et al. Cystatin C inhibits amyloid-beta deposition in Alzheimer's disease mouse models. Nat Genet 2007; 39: 1440–1442.

    Article  CAS  PubMed  Google Scholar 

  134. Eriksson S, Janciauskiene S, Lannfelt L . Alpha 1-antichymotrypsin regulates Alzheimer beta-amyloid peptide fibril formation. Proc Natl Acad Sci USA 1995; 92: 2313–2317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Kocherhans S, Madhusudan A, Doehner J, Breu KS, Nitsch RM, Fritschy JM et al. Reduced reelin expression accelerates amyloid-beta plaque formation and tau pathology in transgenic Alzheimer's disease mice. J Neurosci 2010; 30: 9228–9240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Jucker M, Walker LC . Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. Ann Neurol 2011; 70: 532–540.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Masliah E, Rockenstein E, Veinbergs I, Sagara Y, Mallory M, Hashimoto M et al. Beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease. Proc Natl Acad Sci USA 2001; 98: 12245–12250.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Ono K, Takahashi R, Ikeda T, Yamada M . Cross-seeding effects of amyloid beta-protein and alpha-synuclein. J Neurochem 2012; 122: 883–890.

    Article  CAS  PubMed  Google Scholar 

  139. Fang YS, Tsai KJ, Chang YJ, Kao P, Woods R, Kuo PH et al. Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients. Nat Commun 2014; 5: 4824.

    Article  CAS  PubMed  Google Scholar 

  140. Guerrero-Munoz MJ, Castillo-Carranza DL, Krishnamurthy S, Paulucci-Holthauzen AA, Sengupta U, Lasagna-Reeves CA et al. Amyloid-beta oligomers as a template for secondary amyloidosis in Alzheimer's disease. Neurobiol Dis 2014; 71: 14–23.

    Article  CAS  PubMed  Google Scholar 

  141. Josephs KA, Whitwell JL, Weigand SD, Murray ME, Tosakulwong N, Liesinger AM et al. TDP-43 is a key player in the clinical features associated with Alzheimer's disease. Acta Neuropathol 2014; 127: 811–824.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Hamilton RL . Lewy bodies in Alzheimer's disease: a neuropathological review of 145 cases using alpha-synuclein immunohistochemistry. Brain Pathol 2000; 10: 378–384.

    Article  CAS  PubMed  Google Scholar 

  143. Rapoport M, Dawson HN, Binder LI, Vitek MP, Ferreira A . Tau is essential to beta-amyloid-induced neurotoxicity. Proc Natl Acad Sci USA 2002; 99: 6364–6369.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T et al. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science 2007; 316: 750–754.

    Article  CAS  PubMed  Google Scholar 

  145. Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell 2010; 142: 387–397.

    Article  CAS  PubMed  Google Scholar 

  146. Salter MW, Kalia LV . Src kinases: a hub for NMDA receptor regulation. Nat Rev Neurosci 2004; 5: 317–328.

    Article  CAS  PubMed  Google Scholar 

  147. Nisbet RM, Polanco JC, Ittner LM, Gotz J . Tau aggregation and its interplay with amyloid-beta. Acta Neuropathol 2015; 129: 207–220.

    Article  CAS  PubMed  Google Scholar 

  148. Tu S, Okamoto S, Lipton SA, Xu H . Oligomeric Abeta-induced synaptic dysfunction in Alzheimer's disease. Mol Neurodegener 2014; 9: 48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Spires-Jones TL, Friedman T, Pitstick R, Polydoro M, Roe A, Carlson GA et al. Methylene blue does not reverse existing neurofibrillary tangle pathology in the rTg4510 mouse model of tauopathy. Neurosci Lett 2014; 562: 63–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Spillantini MG, Goedert M . Tau pathology and neurodegeneration. Lancet Neurol 2013; 12: 609–622.

    Article  CAS  PubMed  Google Scholar 

  151. Zempel H, Mandelkow E . Lost after translation: missorting of tau protein and consequences for Alzheimer disease. Trends Neurosci 2014; 37: 721–732.

    Article  CAS  PubMed  Google Scholar 

  152. Frandemiche ML, De Seranno S, Rush T, Borel E, Elie A, Arnal I et al. Activity-dependent tau protein translocation to excitatory synapse is disrupted by exposure to amyloid-beta oligomers. J Neurosci 2014; 34: 6084–6097.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Noble W, Hanger DP, Miller CC, Lovestone S . The importance of tau phosphorylation for neurodegenerative diseases. Front Neurol 2013; 4: 83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Iqbal K, Gong CX, Liu F . Hyperphosphorylation-induced tau oligomers. Front Neurol 2013; 4: 112.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Kins S, Crameri A, Evans DR, Hemmings BA, Nitsch RM, Gotz J . Reduced protein phosphatase 2 A activity induces hyperphosphorylation and altered compartmentalization of tau in transgenic mice. J Biol Chem 2001; 276: 38193–38200.

    CAS  PubMed  Google Scholar 

  156. Yu W, Polepalli J, Wagh D, Rajadas J, Malenka R, Lu B . A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Abeta on synapses and dendritic spines. Hum Mol Genet 2012; 21: 1384–1390.

    Article  CAS  PubMed  Google Scholar 

  157. Mairet-Coello G, Courchet J, Pieraut S, Courchet V, Maximov A, Polleux F . The CAMKK2–AMPK kinase pathway mediates the synaptotoxic effects of Abeta oligomers through Tau phosphorylation. Neuron 2013; 78: 94–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Lee MS, Kwon YT, Li M, Peng J, Friedlander RM, Tsai LH . Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature 2000; 405: 360–364.

    Article  CAS  PubMed  Google Scholar 

  159. Hartigan JA, Johnson GV . Transient increases in intracellular calcium result in prolonged site-selective increases in Tau phosphorylation through a glycogen synthase kinase 3beta-dependent pathway. J Biol Chem 1999; 274: 21395–21401.

    Article  CAS  PubMed  Google Scholar 

  160. Kimura R, Kamino K, Yamamoto M, Nuripa A, Kida T, Kazui H et al. The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between beta-amyloid production and tau phosphorylation in Alzheimer disease. Hum Mol Genet 2007; 16: 15–23.

    Article  CAS  PubMed  Google Scholar 

  161. Del Prete D, Checler F, Chami M . Ryanodine receptors: physiological function and deregulation in Alzheimer disease. Mol Neurodegen 2014; 9: 21.

    Article  CAS  Google Scholar 

  162. Ferreiro E, Oliveira CR, Pereira C . Involvement of endoplasmic reticulum Ca2+ release through ryanodine and inositol 1,4,5-triphosphate receptors in the neurotoxic effects induced by the amyloid-beta peptide. J Neurosci Res 2004; 76: 872–880.

    Article  CAS  PubMed  Google Scholar 

  163. Dreses-Werringloer U, Lambert JC, Vingtdeux V, Zhao H, Vais H, Siebert A et al. A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer's disease risk. Cell 2008; 133: 1149–1161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Gamblin TC, Chen F, Zambrano A, Abraha A, Lagalwar S, Guillozet AL et al. Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease. Proc Natl Acad Sci USA 2003; 100: 10032–10037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Guo JL, Lee VM . Seeding of normal tau by pathological tau conformers drives pathogenesis of Alzheimer-like tangles. J Biol Chem 2011; 286: 15317–15331.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Guo JP, Arai T, Miklossy J, McGeer PL . Abeta and tau form soluble complexes that may promote self aggregation of both into the insoluble forms observed in Alzheimer's disease. Proc Natl Acad Sci USA 2006; 103: 1953–1958.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Hsieh H, Boehm J, Sato C, Iwatsubo T, Tomita T, Sisodia S et al. AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron 2006; 52: 831–843.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Wang HY, Lee DH, D'Andrea MR, Peterson PA, Shank RP, Reitz AB . Beta-amyloid(1-42) binds to alpha7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer's disease pathology. J Biol Chem 2000; 275: 5626–5632.

    Article  CAS  PubMed  Google Scholar 

  169. Larson M, Sherman MA, Amar F, Nuvolone M, Schneider JA, Bennett DA et al. The complex PrP(c)-Fyn couples human oligomeric Abeta with pathological tau changes in Alzheimer's disease. J Neurosci 2012; 32: 16857–71a.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Um JW, Nygaard HB, Heiss JK, Kostylev MA, Stagi M, Vortmeyer A et al. Alzheimer amyloid-beta oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nat Neurosci 2012; 15: 1227–1235.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Kim T, Vidal GS, Djurisic M, William CM, Birnbaum ME, Garcia KC et al. Human LilrB2 is a beta-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer's model. Science 2013; 341: 1399–1404.

    Article  CAS  PubMed  Google Scholar 

  172. Knowles JK, Rajadas J, Nguyen TV, Yang T, LeMieux MC, Vander Griend L et al. The p75 neurotrophin receptor promotes amyloid-beta(1-42)-induced neuritic dystrophy in vitro and in vivo. J Neurosci 2009; 29: 10627–10637.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Cisse M, Checler F . Eph receptors: new players in Alzheimer's disease pathogenesis. Neurobiol Dis 2015; 73: 137–149.

    Article  CAS  PubMed  Google Scholar 

  174. Um JW, Kaufman AC, Kostylev M, Heiss JK, Stagi M, Takahashi H et al. Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer abeta oligomer bound to cellular prion protein. Neuron 2013; 79: 887–902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Roselli F, Tirard M, Lu J, Hutzler P, Lamberti P, Livrea P et al. Soluble beta-amyloid1-40 induces NMDA-dependent degradation of postsynaptic density-95 at glutamatergic synapses. J Neurosci 2005; 25: 11061–11070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL . Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 2007; 27: 2866–2875.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Lustbader JW, Cirilli M, Lin C, Xu HW, Takuma K, Wang N et al. ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease. Science 2004; 304: 448–452.

    Article  CAS  PubMed  Google Scholar 

  178. Manczak M, Calkins MJ, Reddy PH . Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer's disease: implications for neuronal damage. Hum Mol Genet 2011; 20: 2495–2509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Herrup K . The case for rejecting the amyloid cascade hypothesis. Nat Neurosci 2015; 18: 794–799.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Authors would like to thank Magalie Lecourtois and Camille Charbonnier for helpful discussions and Tracey Avequin for editing the manuscript. The authors are supported by grants from the Clinical Research Hospital Program from the French Ministry of Health (GMAJ, PHRC 2008/067), the CNR-MAJ, the JPND PERADES and Inserm.

Author information

Authors and Affiliations

  1. Inserm U1079, Rouen University, Institute for Research and Innovation in Biomedicine, Normandie University, Rouen, France

    D Campion, C Pottier, G Nicolas, K Le Guennec & A Rovelet-Lecrux

  2. National Reference Center for Young Alzheimer Patients (CNR-MAJ), Rouen, France

    D Campion & G Nicolas

  3. Department of Research, Rouvray Psychiatric Hospital, Sotteville-lès-Rouen, France

    D Campion

  4. Normandy Center for Genomic Medicine and Personalized Medicine, Rouen, France

    D Campion, C Pottier, G Nicolas, K Le Guennec & A Rovelet-Lecrux

  5. Department of Genetics, Rouen University Hospital, Rouen, France

    G Nicolas

Authors
  1. D Campion
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Pottier
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G Nicolas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K Le Guennec
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Rovelet-Lecrux
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D Campion.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Campion, D., Pottier, C., Nicolas, G. et al. Alzheimer disease: modeling an Aβ-centered biological network. Mol Psychiatry 21, 861–871 (2016). https://doi.org/10.1038/mp.2016.38

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2016.38

This article is cited by

Search

Advanced search

Quick links