CoChat
Sign Up
Cited by 836Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's Disease

Open access
Kametani, Fuyuki, Hasegawa, Masato·2018·Frontiers in Neuroscience
DOI 10.3389/fnins.2018.00025PMC PMC5797629
Open this paper in CoChat — free accountOpen PDF

Abstract

The so-called amyloid hypothesis, that the accumulation and deposition of oligomeric or fibrillar amyloid β (Aβ) peptide is the primary cause of Alzheimer's disease (AD), has been the mainstream concept underlying AD research for over 20 years. However, all attempts to develop Aβ-targeting drugs to treat AD have ended in failure. Here, we review recent findings indicating that the main factor underlying the development and progression of AD is tau, not Aβ, and we describe the deficiencies of the amyloid hypothesis that have supported the emergence of this idea.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3389/fnins.2018.00025

Cites

35 of 35 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Tau pathology is linked to cognitive decline, may progress more rapidly than Aβ accumulation, and correlates with neuroinflammation, making it a valuable prognostic marker.

    “Numerous studies have linked tau pathology to cognitive decline, with some evidence suggesting it progresses more rapidly than Aβ accumulation and correlates with neuroinflammation, making it a valuable prognostic marker [20, 25–28].”

    From Targeted Nanoparticles for Drug Delivery Across the Blood–Brain Barrier in Early and Late Stages of Alzheimer's Disease: A Review (2026) · cites this paper as [27]

    “The tau hypothesis” links the spread of tau pathology to cognitive and clinical symptoms and says tau lesions may occur earlier than Aβ accumulation. Earlier occurrence does not establish a faster rate of progression. “APP trigger tauopathy” says neuroinflammation may affect tau progression, but does not report a tau–neuroinflammation correlation; neither passage establishes tau as a prognostic marker. Page numbers are unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 117

  1. Baratchi S. Evans J. Tate W. P. Abraham W. C. Connor B. (2012). Secreted amyloid precursor proteins promote proliferation and glial differentiation of adult hippocampal neural progenitor cells. Hippocampus 22, 1517– 1527. 10.1002/hipo.20988 22147523 · DOI
  2. Bardai F. H. Wang L. Mutreja Y. Yenjerla M. Gamblin T. C. Feany M. B. (2018). A conserved cytoskeletal signaling cascade mediates neurotoxicity of FTDP-17 tau mutations in vivo. J. Neurosci. 38, 108– 119. 10.1523/JNEUROSCI.1550-17.2017 29138281 PMC5761430 · DOI · Paper page
  3. Bejanin A. Schonhaut D. R. La Joie R. Kramer J. H. Baker S. L. Sosa N.. (2017). Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer's disease. Brain 140, 3286– 3300. 10.1093/brain/awx243. 29053874 PMC5841139 · DOI · Paper page
  4. Bemiller S. M. McCray T. J. Allan K. Formica S. V. Xu G. Wilson G.. (2017). TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy. Mol. Neurodegener. 12: 74. 10.1186/s13024-017-0216-6 29037207 PMC5644120 · DOI · Paper page
  5. Bentahir M. Nyabi O. Verhamme J. Tolia A. Horré K. Wiltfang J.. (2006). Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J. Neurochem. 96, 732– 742. 10.1111/j.1471-4159.2005.03578.x 16405513 · DOI
  6. Boncristiano S. Calhoun M. E. Howard V. Bondolfi L. Kaeser S. A. Wiederhold K. H.. (2005). Neocortical synaptic bouton number is maintained despite robust amyloid deposition in APP23 transgenic mice. Neurobiol. Aging 26, 607– 613. 10.1016/j.neurobiolaging.2004.06.010 15708435 · DOI · Paper page
  7. Blurton-Jones M. Laferla F. M. (2006). Pathways by which Abeta facilitates tau pathology. Curr. Alzheimer Res. 3, 437– 448. 10.2174/156720506779025242 17168643 · DOI
  8. Braak H. Del Tredici K. (2014). Are cases with tau pathology occurring in the absence of Abeta deposits part of the AD-related pathological process? Acta Neuropathol. 128, 767– 772. 10.1007/s00401-014-1356-1 25359108 · DOI
  9. Bryan K. J. Lee H. Perry G. Smith M. A. Casadesus G. (2009). Transgenic Mouse Models of Alzheimer's Disease: Behavioral Testing and Considerations Methods of Behavior Analysis in Neuroscience. Boca Raton, FL: Taylor & Francis Group, LLC. 21204338
  10. Buckley R. F. Hanseeuw B. Schultz A. P. Vannini P. Aghjayan S. L. Properzi M. J.. (2017). Region-specific association of subjective cognitive decline with tauopathy independent of global beta-amyloid burden. JAMA Neurol. 74, 1455– 1463. 10.1001/jamaneurol.2017.2216 28973551 PMC5774633 · DOI · Paper page
  11. Buée L. Delacourte A. (1999). Comparative biochemistry of tau in progressive supranuclear palsy, corticobasal degeneration, FTDP-17 and Pick's disease. Brain Pathol. 9, 681– 693. 10.1111/j.1750-3639.1999.tb00550.x 10517507 PMC8098140 · DOI
  12. Buxbaum J. D. Liu K. N. Luo Y. Slack J. L. Stocking K. L. Peschon J. J.. (1998). Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. J. Biol. Chem. 273, 27765– 27767. 10.1074/jbc.273.43.27765 9774383 · DOI
  13. Capell A. Grünberg J. Pesold B. Diehlmann A. Citron M. Nixon R.. (1998). The proteolytic fragments of the Alzheimer's disease-associated presenilin-1 form heterodimers and occur as a 100-150-kDa molecular mass complex. J. Biol. Chem. 273, 3205– 3211. 10.1074/jbc.273.6.3205 9452432 · DOI
  14. Chan E. S. Chen C. Cole G. M. Wong B. S. (2015). Differential interaction of Apolipoprotein-E isoforms with insulin receptors modulates brain insulin signaling in mutant human amyloid precursor protein transgenic mice. Sci. Rep. 5: 13842. 10.1038/srep13842 26346625 PMC4561911 · DOI · Paper page
  15. Chaudhary A. R. Berger F. Berger C. L. Hendricks A. G. (2017). Tau directs intracellular trafficking by regulating the forces exerted by kinesin and dynein teams. Traffic. [Epub ahead of print]. 10.1111/tra.12537 29077261 PMC5783771 · DOI · Paper page
  16. Chen F. Gu Y. Hasegawa H. Ruan X. Arawaka S. Fraser P.. (2002). Presenilin 1 mutations activate gamma 42-secretase but reciprocally inhibit epsilon -secretase cleavage of amyloid precursor protein (APP) and S3-Cleavage of Notch. J. Biol. Chem. 277, 36521– 36526. 10.1074/jbc.M205093200 12119298 · DOI
  17. Chételat G. (2013). Alzheimer disease: Abeta-independent processes-rethinking preclinical AD. Nat. Rev. Neurol. 9, 123– 124. 10.1038/nrneurol.2013.21 23399647 PMC3935395 · DOI · Paper page
  18. Chételat G. La Joie R. Villain N. Perrotin A. De La Sayette V. Eustache F.. (2013). Amyloid imaging in cognitively normal individuals, at-risk populations and preclinical Alzheimer's disease. Neuroimage Clin. 2, 356– 365. 10.1016/j.nicl.2013.02.006 24179789 PMC3777672 · DOI
  19. Clavaguera F. Akatsu H. Fraser G. Crowther R. A. Frank S. Hench J.. (2013). Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc. Natl. Acad. Sci. U.S.A. 110, 9535– 9540. 10.1073/pnas.1301175110 23690619 PMC3677441 · DOI
  20. Corder E. H. Saunders A. M. Strittmatter W. J. Schmechel D. E. Gaskell P. C. Small G. W.. (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921– 923. 10.1126/science.8346443 8346443 · DOI · Paper page
  21. Crary J. F. Trojanowski J. Q. Schneider J. A. Abisambra J. F. Abner E. L. Alafuzoff I.. (2014). Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol. 128, 755– 766. 10.1007/s00401-014-1349-0 25348064 PMC4257842 · DOI · Paper page
  22. Crowther R. A. Wischik C. M. (1985). Image reconstruction of the Alzheimer paired helical filament. EMBO J. 4, 3661– 3665. 2419127 PMC554715
  23. Crowther T. Goedert M. Wischik C. M. (1989). The repeat region of microtubule-associated protein tau forms part of the core of the paired helical filament of Alzheimer's disease. Ann. Med. 21, 127– 132. 10.3109/07853898909149199 2504257 · DOI
  24. Cupers P. Orlans I. Craessaerts K. Annaert W. De Strooper B. (2001). The amyloid precursor protein (APP)-cytoplasmic fragment generated by gamma-secretase is rapidly degraded but distributes partially in a nuclear fraction of neurones in culture. J. Neurochem. 78, 1168– 1178. 10.1046/j.1471-4159.2001.00516.x 11553691 · DOI
  25. Davies C. A. Mann D. M. Sumpter P. Q. Yates P. O. (1987). A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer's disease. J. Neurol. Sci. 78, 151– 164. 10.1016/0022-510X(87)90057-8 3572454 · DOI · Paper page
  26. De Strooper B. Saftig P. Craessaerts K. Vanderstichele H. Guhde G. Annaert W.. (1998). Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, 387– 390. 10.1038/34910 9450754 · DOI · Paper page
  27. Delabar J. M. Goldgaber D. Lamour Y. Nicole A. Huret J. L. De Grouchy J.. (1987). Beta amyloid gene duplication in Alzheimer's disease and karyotypically normal Down syndrome. Science 235, 1390– 1392. 10.1126/science.2950593 2950593 · DOI
  28. Deyts C. Clutter M. Herrera S. Jovanovic N. Goddi A. Parent A. T. (2016). Loss of presenilin function is associated with a selective gain of APP function. Elife 5: e15645. 10.7554/eLife.15645 27196744 PMC4915812 · DOI
  29. Doody R. S. Raman R. Farlow M. Iwatsubo T. Vellas B. Joffe S.. (2013). A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N. Engl. J. Med. 369, 341– 350. 10.1056/NEJMoa1210951 23883379 · DOI · Paper page
  30. Duyckaerts C. Braak H. Brion J.-P. Buée L. Del Tredici K. Goedert M.. (2015). PART is part of Alzheimer disease. Acta Neuropathol. 129, 749– 756. 10.1007/s00401-015-1390-7 25628035 PMC4405349 · DOI
  31. Fagan A. M. Mintun M. A. Shah A. R. Aldea P. Roe C. M. Mach R. H.. (2009). Cerebrospinal fluid tau and ptau(181) increase with cortical amyloid deposition in cognitively normal individuals: implications for future clinical trials of Alzheimer's disease. EMBO Mol. Med. 1, 371– 380. 10.1002/emmm.200900048 20049742 PMC2806678 · DOI · Paper page
  32. Francis R. McGrath G. Zhang J. Ruddy D. A. Sym M. Apfeld J.. (2002). aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation. Dev. Cell 3, 85– 97. 10.1016/S1534-5807(02)00189-2 12110170 · DOI
  33. Fu M. M. Holzbaur E. L. (2013). JIP1 regulates the directionality of APP axonal transport by coordinating kinesin and dynein motors. J. Cell Biol. 202, 495– 508. 10.1083/jcb.201302078 23897889 PMC3734084 · DOI
  34. Fulga T. A. Elson-Schwab I. Khurana V. Steinhilb M. L. Spires T. L. Hyman B. T.. (2007). Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo. Nat. Cell Biol. 9, 139– 148. 10.1038/ncb1528 17187063 · DOI · Paper page
  35. Ghosal K. Vogt D. L. Liang M. Shen Y. Lamb B. T. Pimplikar S. W. (2009). Alzheimer's disease-like pathological features in transgenic mice expressing the APP intracellular domain. Proc. Natl. Acad. Sci. U.S.A. 106, 18367– 18372. 10.1073/pnas.0907652106 19837693 PMC2762847 · DOI · Paper page
  36. Giacobini E. Gold G. (2013). Alzheimer disease therapy[mdash]moving from amyloid-[beta] to tau. Nat. Rev. Neurol. 9, 677– 686. 10.1038/nrneurol.2013.223 24217510 · DOI
  37. Glenner G. G. Wong C. W. (1984). Alzheimer's disease: INITIAL report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 120, 885– 890. 10.1016/S0006-291X(84)80190-4 6375662 · DOI · Paper page
  38. Goedert M. (1993). Tau protein and the neurofibrillary pathology of Alzheimer's disease. Trends Neurosci. 16, 460– 465. 10.1016/0166-2236(93)90078-Z 7507619 · DOI
  39. Goedert M. Hasegawa M. (1999). The tauopathies: toward an experimental animal model. Am. J. Pathol. 154, 1– 6. 10.1016/S0002-9440(10)65242-X 9916910 PMC1853453 · DOI
  40. Goedert M. Spillantini M. G. Hasegawa M. Jakes R. Crowther R. A. Klug A. (1996). Molecular dissection of the neurofibrillary lesions of Alzheimer's disease. Cold Spring Harb. Symp. Quant. Biol. 61, 565– 573. 10.1101/SQB.1996.061.01.057 9246483 · DOI
  41. Goedert M. Spillantini M. G. Jakes R. Rutherford D. Crowther R. A. (1989a). Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron 3, 519– 526. 10.1016/0896-6273(89)90210-9 2484340 · DOI · Paper page
  42. Goedert M. Spillantini M. G. Potier M. C. Ulrich J. Crowther R. A. (1989b). Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain. EMBO J. 8, 393– 399. 2498079 PMC400819
  43. Goedert M. Wischik C. M. Crowther R. A. Walker J. E. Klug A. (1988). Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc. Natl. Acad. Sci. U.S.A. 85, 4051– 4055. 10.1073/pnas.85.11.4051 3131773 PMC280359 · DOI · Paper page
  44. Goldsbury C. Mocanu M. M. Thies E. Kaether C. Haass C. Keller P.. (2006). Inhibition of APP trafficking by tau protein does not increase the generation of amyloid-beta peptidesPresenilin/gamma-secretase activity regulates protein clearance from the endocytic recycling compartment Presenilin-1-mediated retention of APP derivatives in early biosynthetic compartments A partial failure of membrane protein turnover may cause Alzheimer's disease: a new hypothesis. Traffic 7, 873– 888. 10.1111/j.1600-0854.2006.00434.x 16734669 · DOI · Paper page
  45. Goutte C. Tsunozaki M. Hale V. A. Priess J. R. (2002). APH-1 is a multipass membrane protein essential for the Notch signaling pathway in Caenorhabditis elegans embryos. Proc. Natl. Acad. Sci. U.S.A. 99, 775– 779. 10.1073/pnas.022523499 11792846 PMC117381 · DOI
  46. Greenberg S. G. Davies P. (1990). A preparation of Alzheimer paired helical filaments that displays distinct tau proteins by polyacrylamide gel electrophoresis. Proc. Natl. Acad. Sci. U.S.A. 87, 5827– 5831. 10.1073/pnas.87.15.5827 2116006 PMC54421 · DOI
  47. Grundke-Iqbal I. Iqbal K. Tung Y. C. Quinlan M. Wisniewski H. M. Binder L. I. (1986). Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc. Natl. Acad. Sci. U.S.A. 83, 4913– 4917. 10.1073/pnas.83.13.4913 3088567 PMC323854 · DOI · Paper page
  48. Hardy J. A. Higgins G. A. (1992). Alzheimer's disease: the amyloid cascade hypothesis. Science 256, 184– 185. 10.1126/science.1566067 1566067 · DOI · Paper page
  49. Hasegawa M. (2016). Molecular mechanisms in the pathogenesis of alzheimer's disease and tauopathies-prion-like seeded aggregation and phosphorylation. Biomolecules 6: e24. 10.3390/biom6020024 27136595 PMC4919919 · DOI
  50. Hasegawa M. Smith M. J. Goedert M. (1998). Tau proteins with FTDP-17 mutations have a reduced ability to promote microtubule assembly. FEBS Lett. 437, 207– 210. 10.1016/S0014-5793(98)01217-4 9824291 · DOI
  51. Hochgräfe K. Sydow A. Mandelkow E. M. (2013). Regulatable transgenic mouse models of Alzheimer disease: onset, reversibility and spreading of Tau pathology. FEBS J. 280, 4371– 4381. 10.1111/febs.12250 23517246 · DOI
  52. Iqbal K. Liu F. Gong C. X. (2016). Tau and neurodegenerative disease: the story so far. Nat. Rev. Neurol. 12, 15– 27. 10.1038/nrneurol.2015.225 26635213 · DOI · Paper page
  53. Ishii T. Kametani F. Haga S. Sato M. (1989). The immunohistochemical demonstration of subsequences of the precursor of the amyloid A4 protein in senile plaques in Alzheimer's disease. Neuropathol. Appl. Neurobiol. 15, 135– 147. 10.1111/j.1365-2990.1989.tb01216.x 2657471 · DOI
  54. Iwatsubo T. Hasegawa M. Ihara Y. (1994). Neuronal and glial tau-positive inclusions in diverse neurologic diseases share common phosphorylation characteristics. Acta Neuropathol. 88, 129– 136. 10.1007/BF00294505 7985493 · DOI
  55. Janson J. Laedtke T. Parisi J. E. O'Brien P. Petersen R. C. Butler P. C. (2004). Increased risk of type 2 diabetes in Alzheimer disease. Diabetes 53, 474– 481. 10.2337/diabetes.53.2.474 14747300 · DOI · Paper page
  56. Jellinger K. A. Alafuzoff I. Attems J. Beach T. G. Cairns N. J. Crary J. F.. (2015). PART, a distinct tauopathy, different from classical sporadic Alzheimer disease. Acta Neuropathol. 129, 757– 762. 10.1007/s00401-015-1407-2 25778618 PMC4534004 · DOI · Paper page
  57. Johnson K. A. Schultz A. Betensky R. A. Becker J. A. Sepulcre J. Rentz D. (2015). Tau PET imaging in aging and early Alzheimer's disease. Ann. Neurol. 79, 110– 119. 10.1002/ana.24546 26505746 PMC4738026 · DOI · Paper page
  58. Kametani F. (2008). epsilon-Secretase: reduction of amyloid precursor protein epsilon-site cleavage in Alzheimer's disease. Curr. Alzheimer Res. 5, 165– 171. 10.2174/156720508783954776 18393801 · DOI
  59. Kametani F. Haga S. (2015). Accumulation of carboxy-terminal fragments of APP increases phosphodiesterase 8B. Neurobiol. Aging 36, 634– 637. 10.1016/j.neurobiolaging.2014.09.029 25457556 · DOI
  60. Kametani F. Usami M. Tanaka K. Kume H. Mori H. (2004). Mutant presenilin (A260V) affects Rab8 in PC12D cell. Neurochem. Int. 44, 313– 320. 10.1016/S0197-0186(03)00176-1 14643748 · DOI
  61. Klevanski M. Herrmann U. Weyer S. W. Fol R. Cartier N. Wolfer D. P.. (2015). The APP intracellular domain is required for normal synaptic morphology, synaptic plasticity, and hippocampus-dependent behavior. J. Neurosci. 35, 16018– 16033. 10.1523/JNEUROSCI.2009-15.2015 26658856 PMC6605503 · DOI · Paper page
  62. Kondo J. Honda T. Mori H. Hamada Y. Miura R. Ogawara M.. (1988). The carboxyl third of tau is tightly bound to paired helical filaments. Neuron 1, 827– 834. 10.1016/0896-6273(88)90130-4 2483105 · DOI
  63. Kopan R. Ilagan M. X. (2004). Gamma-secretase: proteasome of the membrane? Nat. Rev. Mol. Cell Biol. 5, 499– 504. 10.1038/nrm1406 15173829 · DOI
  64. Kosik K. S. Orecchio L. D. Binder L. Trojanowski J. Q. Lee V. M. Lee G. (1988). Epitopes that span the tau molecule are shared with paired helical filaments. Neuron 1, 817– 825. 10.1016/0896-6273(88)90129-8 2483104 · DOI
  65. Kovacs G. G. (2015). Invited review: neuropathology of tauopathies: principles and practice. Neuropathol. Appl. Neurobiol. 41, 3– 23. 10.1111/nan.12208 25495175 · DOI · Paper page
  66. Lammich S. Kojro E. Postina R. Gilbert S. Pfeiffer R. Jasionowski M.. (1999). Constitutive and regulated alpha-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease. Proc. Natl. Acad. Sci. U.S.A. 96, 3922– 3927. 10.1073/pnas.96.7.3922 10097139 PMC22396 · DOI
  67. Leyns C. E. G. Holtzman D. M. (2017). Glial contributions to neurodegeneration in tauopathies. Mol. Neurodegener. 12, 50. 10.1186/s13024-017-0192-x 28662669 PMC5492997 · DOI · Paper page
  68. Li Y. Rinne J. O. Mosconi L. Pirraglia E. Rusinek H. Desanti S.. (2008). Regional analysis of FDG and PIB-PET images in normal aging, mild cognitive impairment, and Alzheimer's disease. Eur. J. Nuclear Med. Mol. Image 35, 2169– 2181. 10.1007/s00259-008-0833-y 18566819 PMC2693402 · DOI · Paper page
  69. Maestre G. Ottman R. Stern Y. Gurland B. Chun M. Tang M. X.. (1995). Apolipoprotein E and Alzheimer's disease: ethnic variation in genotypic risks. Ann. Neurol. 37, 254– 259. 10.1002/ana.410370217 7847867 · DOI
  70. Marciniak E. Leboucher A. Caron E. Ahmed T. Tailleux A. Dumont J.. (2017). Tau deletion promotes brain insulin resistance. J. Exp. Med. 214, 2257– 2269. 10.1084/jem.20161731 28652303 PMC5551570 · DOI · Paper page
  71. Masliah E. Mallory M. Alford M. DeTeresa R. Hansen L. A. Mckeel D. W. Jr.. (2001). Altered expression of synaptic proteins occurs early during progression of Alzheimer's disease. Neurology 56, 127– 129. 10.1212/WNL.56.1.127 11148253 · DOI · Paper page
  72. Masters C. L. Simms G. Weinman N. A. Multhaup G. McDonald B. L. Beyreuther K. (1985). Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc. Natl. Acad. Sci. U.S.A. 82, 4245– 4249. 10.1073/pnas.82.12.4245 3159021 PMC397973 · DOI · Paper page
  73. Miao Y. Chen J. Zhang Q. Sun A. (2010). Deletion of tau attenuates heat shock-induced injury in cultured cortical neurons. J. Neurosci. Res. 88, 102– 110. 10.1002/jnr.22188 19642195 · DOI
  74. Nonaka T. Watanabe S. T. Iwatsubo T. Hasegawa M. (2010). Seeded aggregation and toxicity of {alpha}-synuclein and tau: cellular models of neurodegenerative diseases. J. Biol. Chem. 285, 34885– 34898. 10.1074/jbc.M110.148460 20805224 PMC2966103 · DOI
  75. Nukina N. Ihara Y. (1986). One of the antigenic determinants of paired helical filaments is related to tau protein. J. Biochem. 99, 1541– 1544. 10.1093/oxfordjournals.jbchem.a135625 2423512 · DOI
  76. Okamura N. Yanai K. (2017). Brain imaging: applications of tau PET imaging. Nat. Rev. Neurol. 13, 197– 198. 10.1038/nrneurol.2017.38 28303915 · DOI · Paper page
  77. Oltersdorf T. Ward P. J. Henriksson T. Beattie E. C. Neve R. Lieberburg I.. (1990). The Alzheimer amyloid precursor protein. Identification of a stable intermediate in the biosynthetic/degradative pathway. J. Biol. Chem. 265, 4492– 4497. 1968460
  78. Pera M. Alcolea D. Sánchez-Valle R. Guardia-Laguarta C. Colom-Cadena M. Badiola N.. (2013). Distinct patterns of APP processing in the CNS in autosomal-dominant and sporadic Alzheimer disease. Acta Neuropathol. 125, 201– 213. 10.1007/s00401-012-1062-9 23224319 PMC3623032 · DOI
  79. Poorkaj P. Bird T. D. Wijsman E. Nemens E. Garruto R. M. Anderson L.. (1998). Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann. Neurol. 43, 815– 825. 10.1002/ana.410430617 9629852 · DOI · Paper page
  80. Rapoport M. Dawson H. N. Binder L. I. Vitek M. P. Ferreira A. (2002). Tau is essential to β-amyloid-induced neurotoxicity. Proc. Natl. Acad. Sci. U.S.A. 99, 6364– 6369. 10.1073/pnas.092136199 11959919 PMC122954 · DOI · Paper page
  81. Robakis N. K. Georgakopoulos A. (2014). Allelic interference: a mechanism for trans-dominant transmission of loss of function in the neurodegeneration of Familial Alzheimer's Disease. Neurodegener. Dis. 13, 126– 130. 10.1159/000354241 24081144 PMC3992934 · DOI
  82. Roberson E. D. Scearce-Levie K. Palop J. J. Yan F. Cheng I. H. Wu T. (2007). Reducing endogenous tau ameliorates Amyloid ß-Induced Deficits in an Alzheimer's disease mouse model. Science 316, 750– 754. 10.1126/science.1141736 17478722 · DOI · Paper page
  83. Robert J. Button E. B. Yuen B. Gilmour M. Kang K. Bahrabadi A.. (2017). Clearance of beta-amyloid is facilitated by apolipoprotein E and circulating high-density lipoproteins in bioengineered human vessels. Elife 6: e29595. 10.7554/eLife.29595 28994390 PMC5634784 · DOI
  84. Rodrigues E. M. Weissmiller A. M. Goldstein L. S. (2012). Enhanced beta-secretase processing alters APP axonal transport and leads to axonal defects. Hum. Mol. Genet. 21, 4587– 4601. 10.1093/hmg/dds297 22843498 PMC3471392 · DOI
  85. Rovelet-Lecrux A. Hannequin D. Raux G. Meur N. L. Laquerrière A. Vital A.. (2006). APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat. Genet. 38, 24– 26. 10.1038/ng1718 16369530 · DOI
  86. Roy S. Zhang B. Lee V. M.-Y. Trojanowski J. Q. (2005). Axonal transport defects: a common theme in neurodegenerative diseases. Acta Neuropathol. 109, 5– 13. 10.1007/s00401-004-0952-x 15645263 · DOI
  87. Rusu P. Jansen A. Soba P. Kirsch J. Löwer A. Merdes G.. (2007). Axonal accumulation of synaptic markers in APP transgenic Drosophila depends on the NPTY motif and is paralleled by defects in synaptic plasticity. Eur. J. Neurosci. 25, 1079– 1086. 10.1111/j.1460-9568.2007.05341.x 17331204 · DOI
  88. SantaCruz K. Lewis J. Spires T. Paulson J. Kotilinek L. Ingelsson M.. (2005). Tau suppression in a neurodegenerative mouse model improves memory function. Science 309, 476– 481. 10.1126/science.1113694 16020737 PMC1574647 · DOI · Paper page
  89. Schwarz A. J. Yu P. Miller B. B. Shcherbinin S. Dickson J. Navitsky M.. (2016). Regional profiles of the candidate tau PET ligand 18F-AV-1451 recapitulate key features of Braak histopathological stages. Brain 139, 1539– 1550. 10.1093/brain/aww023 26936940 · DOI · Paper page
  90. Selkoe D. J. (1991). The molecular pathology of Alzheimer's disease. Neuron 6, 487– 498. 10.1016/0896-6273(91)90052-2 1673054 · DOI · Paper page
  91. Shankar G. M. Li S. Mehta T. H. Garcia-Munoz A. Shepardson N. E. Smith I.. (2008). Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat. Med. 14, 837– 842. 10.1038/nm1782 18568035 PMC2772133 · DOI · Paper page
  92. Shipton O. A. Leitz J. R. Dworzak J. Acton C. E. J. Tunbridge E. M. Denk F.. (2011). Tau Protein Is Required for Amyloid β-induced impairment of hippocampal long-term potentiation. J. Neurosci. 31, 1688– 1692. 10.1523/JNEUROSCI.2610-10.2011 21289177 PMC3836238 · DOI · Paper page
  93. Spillantini M. G. Goedert M. Crowther R. A. Murrell J. R. Farlow M. R. Ghetti B. (1997). Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments. Proc. Natl. Acad. Sci. U.S.A. 94, 4113– 4118. 10.1073/pnas.94.8.4113 9108114 PMC20577 · DOI
  94. Spillantini M. G. Murrell J. R. Goedert M. Farlow M. R. Klug A. Ghetti B. (1998). Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc. Natl. Acad. Sci. USA. 95, 7737– 7741. 10.1073/pnas.95.13.7737 9636220 PMC22742 · DOI · Paper page
  95. SvedruŽić Ž. M. Popović K. Šendula-Jengić V. (2015). Decrease in catalytic capacity of gamma-secretase can facilitate pathogenesis in sporadic and Familial Alzheimer's disease. Mol. Cell. Neurosci. 67, 55– 65. 10.1016/j.mcn.2015.06.002 26051801 · DOI
  96. Szpankowski L. Encalada S. E. Goldstein L. S. (2012). Subpixel colocalization reveals amyloid precursor protein-dependent kinesin-1 and dynein association with axonal vesicles. Proc. Natl. Acad. Sci. U.S.A. 109, 8582– 8587. 10.1073/pnas.1120510109 22582169 PMC3365224 · DOI
  97. Tai L. M. Ghura S. Koster K. P. Liakaite V. Maienschein-Cline M. Kanabar P.. (2015). APOE-modulated Aβ-induced neuroinflammation in Alzheimer's disease: current landscape, novel data, and future perspective. J. Neurochem. 133, 465– 488. 10.1111/jnc.13072 25689586 PMC4400246 · DOI · Paper page
  98. Takahashi M. Miyata H. Kametani F. Nonaka T. Akiyama H. Hisanaga S.-I.. (2015). Extracellular association of APP and tau fibrils induces intracellular aggregate formation of tau. Acta Neuropathol. 129, 895– 907. 10.1007/s00401-015-1415-2 25869641 PMC4436700 · DOI
  99. Takasugi N. Tomita T. Hayashi I. Tsuruoka M. Niimura M. Takahashi Y.. (2003). The role of presenilin cofactors in the gamma-secretase complex. Nature 422, 438– 441. 10.1038/nature01506 12660785 · DOI
  100. Tamayev R. Matsuda S. Arancio O. D'adamio L. (2012). beta- but not gamma-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia. EMBO Mol. Med. 4, 171– 179. 10.1002/emmm.201100195 22170863 PMC3376850 · DOI · Paper page
  101. Taniguchi-Watanabe S. Arai T. Kametani F. Nonaka T. Masuda-Suzukake M. Tarutani A.. (2016). Biochemical classification of tauopathies by immunoblot, protein sequence and mass spectrometric analyses of sarkosyl-insoluble and trypsin-resistant tau. Acta Neuropathol. 131, 267– 280. 10.1007/s00401-015-1503-3 26538150 PMC4713716 · DOI · Paper page
  102. Tesco G. Ginestroni A. Hiltunen M. Kim M. Dolios G. Hyman B. T.. (2005). APP substitutions V715F and L720P alter PS1 conformation and differentially affect Abeta and AICD generation. J. Neurochem. 95, 446– 456. 10.1111/j.1471-4159.2005.03381.x 16086682 · DOI
  103. Walker E. S. Martinez M. Brunkan A. L. Goate A. (2005). Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios. J. Neurochem. 92, 294– 301. 10.1111/j.1471-4159.2004.02858.x 15663477 · DOI
  104. Weidemann A. Eggert S. Reinhard F. B. Vogel M. Paliga K. Baier G.. (2002). A novel epsilon-cleavage within the transmembrane domain of the Alzheimer amyloid precursor protein demonstrates homology with Notch processing. Biochemistry 41, 2825– 2835. 10.1021/bi015794o 11851430 · DOI
  105. Wiley J. C. Hudson M. Kanning K. C. Schecterson L. C. Bothwell M. (2005). Familial Alzheimer's disease mutations inhibit gamma-secretase-mediated liberation of beta-amyloid precursor protein carboxy-terminal fragment. J. Neurochem. 94, 1189– 1201. 10.1111/j.1471-4159.2005.03266.x 15992373 · DOI
  106. William C. M. Andermann M. L. Goldey G. J. Roumis D. K. Reid R. C. Shatz C. J.. (2012). Synaptic plasticity defect following visual deprivation in Alzheimer's disease model transgenic mice. J. Neurosci. 32, 8004– 8011. 10.1523/JNEUROSCI.5369-11.2012 22674275 PMC3493160 · DOI
  107. Wischik C. M. Novak M. Edwards P. C. Klug A. Tichelaar W. Crowther R. A. (1988a). Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc. Natl. Acad. Sci. U.S.A. 85, 4884– 4888. 10.1073/pnas.85.13.4884 2455299 PMC280541 · DOI
  108. Wischik C. M. Novak M. Thøgersen H. C. Edwards P. C. Runswick M. J. Jakes R.. (1988b). Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc. Natl. Acad. Sci. U.S.A. 85, 4506– 4510. 10.1073/pnas.85.12.4506 3132715 PMC280459 · DOI · Paper page
  109. Woodruff G. Reyna S. M. Dunlap M. Van Der Kant R. Callender J. A. Young J. E.. (2016). Defective transcytosis of APP and lipoproteins in human iPSC-derived neurons with familial Alzheimer's disease mutations. Cell Rep. 17, 759– 773. 10.1016/j.celrep.2016.09.034 27732852 PMC5796664 · DOI
  110. Xia D. Watanabe H. Wu B. Lee S. H. Li Y. Tsvetkov E.. (2015). Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer's disease. Neuron 85, 967– 981. 10.1016/j.neuron.2015.02.010 25741723 PMC4358812 · DOI
  111. Xu T. H. Yan Y. Kang Y. Jiang Y. Melcher K. Xu H. E. (2016a). Alzheimer's disease-associated mutations increase amyloid precursor protein resistance to gamma-secretase cleavage and the Abeta42/Abeta40 ratio. Cell Discov. 2: 16026. 10.1038/celldisc.2016.26 27625790 PMC4994064 · DOI
  112. Xu W. Weissmiller A. M. White J. A. II. Fang F. Wang X. Wu Y.. (2016b). Amyloid precursor protein-mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration. J. Clin. Invest. 126, 1815– 1833. 10.1172/JCI82409 27064279 PMC4855914 · DOI
  113. Yamada K. Patel T. K. Hochgräfe K. Mahan T. E. Jiang H. Stewart F. R. (2015). Analysis of in vivo turnover of tau in a mousemodel of tauopathy. Mol. Neurodegener. 10, 55 10.1186/s13024-015-0052-5 26502977 PMC4621881 · DOI
  114. Yoshikawa K. Aizawa T. Hayashi Y. (1992). Degeneration in vitro of post-mitotic neurons overexpressing the Alzheimer amyloid protein precursor. Nature 359, 64– 67. 10.1038/359064a0 1301020 · DOI
  115. Yu G. Nishimura M. Arawaka S. Levitan D. Zhang L. Tandon A.. (2000). Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature 407, 48– 54. 10.1038/35024009 10993067 · DOI
  116. Zempel H. Mandelkow E. (2014). Lost after translation: missorting of Tau protein and consequences for Alzheimer disease. Trends Neurosci. 37, 721– 732. 10.1016/j.tins.2014.08.004 25223701 · DOI
  117. Zhou L. McInnes J. Wierda K. Holt M. Herrmann A. G. Jackson R. J.. (2017). Tau association with synaptic vesicles causes presynaptic dysfunction. Nat. Commun. 8: 15295. 10.1038/ncomms15295 28492240 PMC5437271 · DOI · Paper page

Cited by

Sorted by citations

Authors
Kametani, F., & Hasegawa, M.
Affiliations
Tokyo Metropolitan Institute of Medical Science (JP)
Corresponding author
  • Kametani, Fuyuki
  • Hasegawa, Masato
ORCID
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2018-01-30
Volume
12
Pages
25-25
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2018.00025
PMC
PMC5797629
OpenAlex
W2790798430
Cited by
836
References
35
Citations by year
2026: 37 · 2025: 69 · 2024: 112 · 2023: 102 · 2022: 148 · 2021: 123 · 2020: 143 · 2019: 78 · 2018: 23
FWCI
12.04
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Japan Agency for Medical Research and Development (JP14533254)
  • Japan Society for the Promotion of Science (23228004, JP26117005, 26293084)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, amyloid hypothesis, tau hypothesis, amyloid-beta, tau protein, drug failure, pathogenesis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review