Skip to main content
SpringerLink
Log in

Amyloid-β and Tau at the Crossroads of Alzheimer’s Disease

  • Chapter
  • First Online:
Book cover Tau Biology

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1184))

Abstract

Alzheimer’s disease (AD) is the most common form of dementia characterized neuropathologically by senile plaques and neurofibrillary tangles (NFTs). Early breakthroughs in AD research led to the discovery of amyloid-β as the major component of senile plaques and tau protein as the major component of NFTs. Shortly following the identification of the amyloid-β (Aβ) peptide was the discovery that a genetic mutation in the amyloid precursor protein (APP), a type1 transmembrane protein, can be a cause of autosomal dominant familial AD (fAD). These discoveries, coupled with other breakthroughs in cell biology and human genetics, have led to a theory known as the “amyloid hypothesis”, which postulates that amyloid-β is the predominant driving factor in AD development. Nonetheless, more recent advances in imaging analysis, biomarkers and mouse models are now redefining this original hypothesis, as it is likely amyloid-β, tau and other pathophysiological mechanism such as inflammation, come together at a crossroads that ultimately leads to the development of AD.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Maurer K, Volk S, Gerbaldo H. Auguste D and Alzheimer’s disease. Lancet. 1997;349(9064):1546–9.

    Article  CAS  PubMed  Google Scholar 

  2. Glenner GG, Wong CW. Alzheimer’s disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun. 1984;122(3):1131–5.

    Article  CAS  PubMed  Google Scholar 

  3. Glenner GG, Wong CW, Quaranta V, Eanes ED. The amyloid deposits in Alzheimer’s disease: their nature and pathogenesis. Appl Pathol. 1984;2(6):357–69.

    CAS  PubMed  Google Scholar 

  4. Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A. 1985;82(12):4245–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lai F, Williams RS. A prospective study of Alzheimer disease in Down syndrome. Arch Neurol. 1989;46(8):849–53.

    Article  CAS  PubMed  Google Scholar 

  6. Wisniewski KE, Wisniewski HM, Wen GY. Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome. Ann Neurol. 1985;17(3):278–82.

    Article  CAS  PubMed  Google Scholar 

  7. Goldgaber D, Lerman MI, McBride OW, Saffiotti U, Gajdusek DC. Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer’s disease. Science. 1987;235(4791):877–80.

    Article  CAS  PubMed  Google Scholar 

  8. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, et al. The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987;325(6106):733–6.

    Article  CAS  PubMed  Google Scholar 

  9. Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256(5054):184–5.

    Article  CAS  PubMed  Google Scholar 

  10. Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov. 2011;10(9):698–712.

    Article  CAS  PubMed  Google Scholar 

  11. Perrin RJ, Fagan AM, Holtzman DM. Multimodal techniques for diagnosis and prognosis of Alzheimer’s disease. Nature. 2009;461(7266):916–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Dickson TC, Vickers JC. The morphological phenotype of beta-amyloid plaques and associated neuritic changes in Alzheimer’s disease. Neuroscience. 2001;105(1):99–107.

    Article  CAS  PubMed  Google Scholar 

  13. Gomez-Isla T, Spires T, De Calignon A, Hyman BT. Neuropathology of Alzheimer’s disease. Handb Clin Neurol. 2008;89:233–43.

    Article  PubMed  Google Scholar 

  14. Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT. Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med. 2011;1(1):a006189.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Glenner GG, Wong CW. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 1984;120(3):885–90.

    Article  CAS  PubMed  Google Scholar 

  16. Kidd M. Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature. 1963;197:192–3.

    Article  CAS  PubMed  Google Scholar 

  17. Joachim CL, Morris JH, Selkoe DJ, Kosik KS. Tau epitopes are incorporated into a range of lesions in Alzheimer’s disease. J Neuropathol Exp Neurol. 1987;46(6):611–22.

    Article  CAS  PubMed  Google Scholar 

  18. Witman GB, Cleveland DW, Weingarten MD, Kirschner MW. Tubulin requires tau for growth onto microtubule initiating sites. Proc Natl Acad Sci U S A. 1976;73(11):4070–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci. 2001;24:1121–59.

    Article  CAS  PubMed  Google Scholar 

  20. Biernat J, Mandelkow EM, Schroter C, Lichtenberg-Kraag B, Steiner B, Berling B, et al. The switch of tau protein to an Alzheimer-like state includes the phosphorylation of two serine-proline motifs upstream of the microtubule binding region. EMBO J. 1992;11(4):1593–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Goedert M, Jakes R, Crowther RA, Cohen P, Vanmechelen E, Vandermeeren M, et al. Epitope mapping of monoclonal antibodies to the paired helical filaments of Alzheimer’s disease: identification of phosphorylation sites in tau protein. Biochem J. 1994;301(Pt 3):871–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Matsuo ES, Shin RW, Billingsley ML, Van de Voorde A, O’Connor M, Trojanowski JQ, et al. Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer’s disease paired helical filament tau. Neuron. 1994;13(4):989–1002.

    Article  CAS  PubMed  Google Scholar 

  23. Braak H, Braak E, Grundke-Iqbal I, Iqbal K. Occurrence of neuropil threads in the senile human brain and in Alzheimer’s disease: a third location of paired helical filaments outside of neurofibrillary tangles and neuritic plaques. Neurosci Lett. 1986;65(3):351–5.

    Article  CAS  PubMed  Google Scholar 

  24. Braak H, Braak E. Neuropil threads occur in dendrites of tangle-bearing nerve cells. Neuropathol Appl Neurobiol. 1988;14(1):39–44.

    Article  CAS  PubMed  Google Scholar 

  25. Perry G, Kawai M, Tabaton M, Onorato M, Mulvihill P, Richey P, et al. Neuropil threads of Alzheimer’s disease show a marked alteration of the normal cytoskeleton. J Neurosci. 1991;11(6):1748–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Schmidt ML, Gur RE, Gur RC, Trojanowski JQ. Intraneuronal and extracellular neurofibrillary tangles exhibit mutually exclusive cytoskeletal antigens. Ann Neurol. 1988;23(2):184–9.

    Article  CAS  PubMed  Google Scholar 

  27. Van Broeckhoven C, Haan J, Bakker E, Hardy JA, Van Hul W, Wehnert A, et al. Amyloid beta protein precursor gene and hereditary cerebral hemorrhage with amyloidosis (Dutch). Science. 1990;248(4959):1120–2.

    Article  PubMed  Google Scholar 

  28. Levy E, Carman MD, Fernandez-Madrid IJ, Power MD, Lieberburg I, van Duinen SG, et al. Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science. 1990;248(4959):1124–6.

    Article  CAS  PubMed  Google Scholar 

  29. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature. 1991;349(6311):704–6.

    Article  CAS  PubMed  Google Scholar 

  30. Chartier-Harlin MC, Crawford F, Houlden H, Warren A, Hughes D, Fidani L, et al. Early-onset Alzheimer’s disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature. 1991;353(6347):844–6.

    Article  CAS  PubMed  Google Scholar 

  31. Murrell J, Farlow M, Ghetti B, Benson MD. A mutation in the amyloid precursor protein associated with hereditary Alzheimer’s disease. Science. 1991;254(5028):97–9.

    Article  CAS  PubMed  Google Scholar 

  32. Haass C, Hung AY, Selkoe DJ, Teplow DB. Mutations associated with a locus for familial Alzheimer’s disease result in alternative processing of amyloid beta-protein precursor. J Biol Chem. 1994;269(26):17741–8.

    CAS  PubMed  Google Scholar 

  33. Suzuki N, Cheung TT, Cai XD, Odaka A, Otvos L Jr, Eckman C, et al. An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science. 1994;264(5163):1336–40.

    Article  CAS  PubMed  Google Scholar 

  34. Mullan M, Crawford F, Axelman K, Houlden H, Lilius L, Winblad B, et al. A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet. 1992;1(5):345–7.

    Article  CAS  PubMed  Google Scholar 

  35. Cai XD, Golde TE, Younkin SG. Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. Science. 1993;259(5094):514–6.

    Article  CAS  PubMed  Google Scholar 

  36. Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, et al. Mutation of the beta-amyloid precursor protein in familial Alzheimer’s disease increases beta-protein production. Nature. 1992;360(6405):672–4.

    Article  CAS  PubMed  Google Scholar 

  37. Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, Laquerriere A, Vital A, et al. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet. 2006;38(1):24–6.

    Article  CAS  PubMed  Google Scholar 

  38. Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature. 2012;488(7409):96–9.

    Article  CAS  PubMed  Google Scholar 

  39. Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, et al. The ‘Arctic’ APP mutation (E693G) causes Alzheimer’s disease by enhanced Abeta protofibril formation. Nat Neurosci. 2001;4(9):887–93.

    Article  CAS  PubMed  Google Scholar 

  40. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002;416(6880):535–9.

    Article  CAS  PubMed  Google Scholar 

  41. Dodart JC, Bales KR, Gannon KS, Greene SJ, DeMattos RB, Mathis C, et al. Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer’s disease model. Nat Neurosci. 2002;5(5):452–7.

    Article  CAS  PubMed  Google Scholar 

  42. Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, et al. A specific amyloid-beta protein assembly in the brain impairs memory. Nature. 2006;440(7082):352–7.

    Article  CAS  PubMed  Google Scholar 

  43. Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, et al. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med. 1996;2(8):864–70.

    Article  CAS  PubMed  Google Scholar 

  44. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature. 1995;375(6534):754–60.

    Article  CAS  PubMed  Google Scholar 

  45. Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, et al. Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature. 1995;376(6543):775–8.

    Article  CAS  PubMed  Google Scholar 

  46. Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, et al. Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nat Med. 1997;3(1):67–72.

    Article  CAS  PubMed  Google Scholar 

  47. Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature. 1999;398(6727):513–7.

    Article  CAS  PubMed  Google Scholar 

  48. Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, Tandon A, et al. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature. 2000;407(6800):48–54.

    Article  CAS  PubMed  Google Scholar 

  49. Francis R, McGrath G, Zhang J, Ruddy DA, Sym M, Apfeld J, et al. aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation. Dev Cell. 2002;3(1):85–97.

    Article  CAS  PubMed  Google Scholar 

  50. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993;90(5):1977–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Schmechel DE, Saunders AM, Strittmatter WJ, Crain BJ, Hulette CM, Joo SH, et al. Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Natl Acad Sci U S A. 1993;90(20):9649–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261(5123):921–3.

    Article  CAS  PubMed  Google Scholar 

  53. 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(9):903–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Holtzman DM, Fagan AM, Mackey B, Tenkova T, Sartorius L, Paul SM, et al. Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer’s disease model. Ann Neurol. 2000;47(6):739–47.

    Article  CAS  PubMed  Google Scholar 

  55. Fagan AM, Watson M, Parsadanian M, Bales KR, Paul SM, Holtzman DM. Human and murine ApoE markedly alters A beta metabolism before and after plaque formation in a mouse model of Alzheimer’s disease. Neurobiol Dis. 2002;9(3):305–18.

    Article  CAS  PubMed  Google Scholar 

  56. Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017;549(7673):523–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012;367(9):795–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Fagan AM, Mintun MA, Mach RH, Lee SY, Dence CS, Shah AR, et al. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol. 2006;59(3):512–9.

    Article  CAS  PubMed  Google Scholar 

  59. Jack CR Jr, Vemuri P, Wiste HJ, Weigand SD, Aisen PS, Trojanowski JQ, et al. Evidence for ordering of Alzheimer disease biomarkers. Arch Neurol. 2011;68(12):1526–35.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, Holtzman DM. Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol. 2007;64(3):343–9.

    Article  PubMed  Google Scholar 

  61. Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 2010;9(1):119–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Jagust WJ, Landau SM, Shaw LM, Trojanowski JQ, Koeppe RA, Reiman EM, et al. Relationships between biomarkers in aging and dementia. Neurology. 2009;73(15):1193–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Doraiswamy PM, Sperling RA, Coleman RE, Johnson KA, Reiman EM, Davis MD, et al. Amyloid-beta assessed by florbetapir F 18 PET and 18-month cognitive decline: a multicenter study. Neurology. 2012;79(16):1636–44.

    Article  CAS  PubMed  Google Scholar 

  64. Doraiswamy PM, Sperling RA, Johnson K, Reiman EM, Wong TZ, Sabbagh MN, et al. Florbetapir F 18 amyloid PET and 36-month cognitive decline: a prospective multicenter study. Mol Psychiatry. 2014;19(9):1044–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ong K, Villemagne VL, Bahar-Fuchs A, Lamb F, Chetelat G, Raniga P, et al. (18)F-florbetaben Abeta imaging in mild cognitive impairment. Alzheimers Res Ther. 2013;5(1):4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Sabuncu MR, Desikan RS, Sepulcre J, Yeo BT, Liu H, Schmansky NJ, et al. The dynamics of cortical and hippocampal atrophy in Alzheimer disease. Arch Neurol. 2011;68(8):1040–8.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Chetelat G, Villemagne VL, Villain N, Jones G, Ellis KA, Ames D, et al. Accelerated cortical atrophy in cognitively normal elderly with high beta-amyloid deposition. Neurology. 2012;78(7):477–84.

    Article  CAS  PubMed  Google Scholar 

  68. Chetelat G, Villemagne VL, Bourgeat P, Pike KE, Jones G, Ames D, et al. Relationship between atrophy and beta-amyloid deposition in Alzheimer disease. Ann Neurol. 2010;67(3):317–24.

    CAS  PubMed  Google Scholar 

  69. Archer HA, Edison P, Brooks DJ, Barnes J, Frost C, Yeatman T, et al. Amyloid load and cerebral atrophy in Alzheimer’s disease: an 11C-PIB positron emission tomography study. Ann Neurol. 2006;60(1):145–7.

    Article  PubMed  Google Scholar 

  70. Andrews KA, Frost C, Modat M, Cardoso MJ, Rowe CC, Villemagne V, et al. Acceleration of hippocampal atrophy rates in asymptomatic amyloidosis. Neurobiol Aging. 2016;39:99–107.

    Article  CAS  PubMed  Google Scholar 

  71. Dore V, Villemagne VL, Bourgeat P, Fripp J, Acosta O, Chetelat G, et al. Cross-sectional and longitudinal analysis of the relationship between Abeta deposition, cortical thickness, and memory in cognitively unimpaired individuals and in Alzheimer disease. JAMA Neurol. 2013;70(7):903–11.

    Article  PubMed  Google Scholar 

  72. Sperling RA, Johnson KA, Doraiswamy PM, Reiman EM, Fleisher AS, Sabbagh MN, et al. Amyloid deposition detected with florbetapir F 18 ((18)F-AV-45) is related to lower episodic memory performance in clinically normal older individuals. Neurobiol Aging. 2013;34(3):822–31.

    Article  CAS  PubMed  Google Scholar 

  73. Andrews KA, Modat M, Macdonald KE, Yeatman T, Cardoso MJ, Leung KK, et al. Atrophy rates in asymptomatic amyloidosis: implications for Alzheimer prevention trials. PLoS One. 2013;8(3):e58816.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239–59.

    Article  CAS  PubMed  Google Scholar 

  75. Gomez-Isla T, Hollister R, West H, Mui S, Growdon JH, Petersen RC, et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol. 1997;41(1):17–24.

    Article  CAS  PubMed  Google Scholar 

  76. Arriagada PV, Marzloff K, Hyman BT. Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer’s disease. Neurology. 1992;42(9):1681–8.

    Article  CAS  PubMed  Google Scholar 

  77. Price JL, Davis PB, Morris JC, White DL. The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer’s disease. Neurobiol Aging. 1991;12(4):295–312.

    Article  CAS  PubMed  Google Scholar 

  78. Price JL, Morris JC. Tangles and plaques in nondemented aging and "preclinical" Alzheimer’s disease. Ann Neurol. 1999;45(3):358–68.

    Article  CAS  PubMed  Google Scholar 

  79. Johnson KA, Schultz A, Betensky RA, Becker JA, Sepulcre J, Rentz D, et al. Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann Neurol. 2016;79(1):110–9.

    Article  PubMed  Google Scholar 

  80. Brier MR, Gordon B, Friedrichsen K, McCarthy J, Stern A, Christensen J, et al. Tau and Abeta imaging, CSF measures, and cognition in Alzheimer’s disease. Sci Transl Med. 2016;8(338):338ra66.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Bejanin A, Schonhaut DR, La Joie R, Kramer JH, Baker SL, Sosa N, et al. Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer’s disease. Brain. 2017;140(12):3286–300.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Braak H, Del Tredici K. The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol. 2011;121(2):171–81.

    Article  PubMed  Google Scholar 

  83. Price JL, McKeel DW Jr, Buckles VD, Roe CM, Xiong C, Grundman M, et al. Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease. Neurobiol Aging. 2009;30(7):1026–36.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Nelson PT, Braak H, Markesbery WR. Neuropathology and cognitive impairment in Alzheimer disease: a complex but coherent relationship. J Neuropathol Exp Neurol. 2009;68(1):1–14.

    Article  CAS  PubMed  Google Scholar 

  85. Vos SJ, Xiong C, Visser PJ, Jasielec MS, Hassenstab J, Grant EA, et al. Preclinical Alzheimer’s disease and its outcome: a longitudinal cohort study. Lancet Neurol. 2013;12(10):957–65.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Roe CM, Fagan AM, Grant EA, Hassenstab J, Moulder KL, Maue Dreyfus D, et al. Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later. Neurology. 2013;80(19):1784–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O, et al. Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol. 2013;12(4):357–67.

    Article  CAS  PubMed  Google Scholar 

  88. Chen X, Li M, Wang S, Zhu H, Xiong Y, Liu X. Pittsburgh compound B retention and progression of cognitive status--a meta-analysis. Eur J Neurol. 2014;21(8):1060–7.

    Article  CAS  PubMed  Google Scholar 

  89. Donohue MC, Sperling RA, Petersen R, Sun CK, Weiner MW, Aisen PS. Association between elevated brain amyloid and subsequent cognitive decline among cognitively normal persons. JAMA. 2017;317(22):2305–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Combs B, Hamel C, Kanaan NM. Pathological conformations involving the amino terminus of tau occur early in Alzheimer’s disease and are differentially detected by monoclonal antibodies. Neurobiol Dis. 2016;94:18–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kanaan NM, Morfini G, Pigino G, LaPointe NE, Andreadis A, Song Y, et al. Phosphorylation in the amino terminus of tau prevents inhibition of anterograde axonal transport. Neurobiol Aging. 2012;33(4):826.e15–30.

    Article  CAS  Google Scholar 

  92. Abraha A, Ghoshal N, Gamblin TC, Cryns V, Berry RW, Kuret J, et al. C-terminal inhibition of tau assembly in vitro and in Alzheimer’s disease. J Cell Sci. 2000;113(Pt 21):3737–45.

    CAS  PubMed  Google Scholar 

  93. Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009;11(7):909–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Iba M, Guo JL, McBride JD, Zhang B, Trojanowski JQ, Lee VM. Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer’s-like tauopathy. J Neurosci. 2013;33(3):1024–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Gomez-Isla T, Price JL, McKeel DW Jr, Morris JC, Growdon JH, Hyman BT. Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. J Neurosci. 1996;16(14):4491–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. West MJ, Coleman PD, Flood DG, Troncoso JC. Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease. Lancet. 1994;344(8925):769–72.

    Article  CAS  PubMed  Google Scholar 

  97. Mattsson N, Insel PS, Nosheny R, Tosun D, Trojanowski JQ, Shaw LM, et al. Emerging beta-amyloid pathology and accelerated cortical atrophy. JAMA Neurol. 2014;71(6):725–34.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Gotz J, Chen F, van Dorpe J, Nitsch RM. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science. 2001;293(5534):1491–5.

    Article  CAS  PubMed  Google Scholar 

  99. Bolmont T, Clavaguera F, Meyer-Luehmann M, Herzig MC, Radde R, Staufenbiel M, et al. Induction of tau pathology by intracerebral infusion of amyloid-beta -containing brain extract and by amyloid-beta deposition in APP x Tau transgenic mice. Am J Pathol. 2007;171(6):2012–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science. 2001;293(5534):1487–91.

    Article  CAS  PubMed  Google Scholar 

  101. 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(4):1977–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Bennett RE, DeVos SL, Dujardin S, Corjuc B, Gor R, Gonzalez J, et al. Enhanced Tau Aggregation in the Presence of Amyloid beta. Am J Pathol. 2017;187(7):1601–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Guo JL, Narasimhan S, Changolkar L, He Z, Stieber A, Zhang B, et al. Unique pathological tau conformers from Alzheimer’s brains transmit tau pathology in nontransgenic mice. J Exp Med. 2016;213(12):2635–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. He Z, Guo JL, McBride JD, Narasimhan S, Kim H, Changolkar L, et al. Amyloid-beta plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med. 2018;24(1):29–38.

    Article  CAS  PubMed  Google Scholar 

  105. Busciglio J, Lorenzo A, Yeh J, Yankner BA. beta-amyloid fibrils induce tau phosphorylation and loss of microtubule binding. Neuron. 1995;14(4):879–88.

    Article  CAS  PubMed  Google Scholar 

  106. Arioka M, Tsukamoto M, Ishiguro K, Kato R, Sato K, Imahori K, et al. Tau protein kinase II is involved in the regulation of the normal phosphorylation state of tau protein. J Neurochem. 1993;60(2):461–8.

    Article  CAS  PubMed  Google Scholar 

  107. Rapoport M, Dawson HN, Binder LI, Vitek MP, Ferreira A. Tau is essential to beta -amyloid-induced neurotoxicity. Proc Natl Acad Sci U S A. 2002;99(9):6364–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Zempel H, Luedtke J, Kumar Y, Biernat J, Dawson H, Mandelkow E, et al. Amyloid-beta oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin. EMBO J. 2013;32(22):2920–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. King ME, Kan HM, Baas PW, Erisir A, Glabe CG, Bloom GS. Tau-dependent microtubule disassembly initiated by prefibrillar beta-amyloid. J Cell Biol. 2006;175(4):541–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Shipton OA, Leitz JR, Dworzak J, Acton CE, Tunbridge EM, Denk F, et al. Tau protein is required for amyloid {beta}-induced impairment of hippocampal long-term potentiation. J Neurosci. 2011;31(5):1688–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. 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(3):387–97.

    Article  CAS  PubMed  Google Scholar 

  112. 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(5825):750–4.

    Article  CAS  PubMed  Google Scholar 

  113. Leroy K, Ando K, Laporte V, Dedecker R, Suain V, Authelet M, et al. Lack of tau proteins rescues neuronal cell death and decreases amyloidogenic processing of APP in APP/PS1 mice. Am J Pathol. 2012;181(6):1928–40.

    Article  CAS  PubMed  Google Scholar 

  114. Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, et al. TREM2 variants in Alzheimer’s disease. N Engl J Med. 2013;368(2):117–27.

    Article  CAS  PubMed  Google Scholar 

  115. 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. N Engl J Med. 2013;368(2):107–16.

    Article  CAS  PubMed  Google Scholar 

  116. Takahashi K, Rochford CD, Neumann H. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med. 2005;201(4):647–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Piccio L, Buonsanti C, Mariani M, Cella M, Gilfillan S, Cross AH, et al. Blockade of TREM-2 exacerbates experimental autoimmune encephalomyelitis. Eur J Immunol. 2007;37(5):1290–301.

    Article  CAS  PubMed  Google Scholar 

  118. Ulrich JD, Finn MB, Wang Y, Shen A, Mahan TE, Jiang H, et al. Altered microglial response to Abeta plaques in APPPS1-21 mice heterozygous for TREM2. Mol Neurodegener. 2014;9:20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. 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(6):1061–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Wang Y, Ulland TK, Ulrich JD, Song W, Tzaferis JA, Hole JT, et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J Exp Med. 2016;213(5):667–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Yuan P, Condello C, Keene CD, Wang Y, Bird TD, Paul SM, et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron. 2016;92(1):252–64.

    Article  CAS  PubMed  Google Scholar 

  122. Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci. 2015;18(11):1584–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT. Regulation of tau pathology by the microglial fractalkine receptor. Neuron. 2010;68(1):19–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Maphis N, Xu G, Kokiko-Cochran ON, Jiang S, Cardona A, Ransohoff RM, et al. Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain. 2015;138(Pt 6):1738–55.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Nagele RG, Wegiel J, Venkataraman V, Imaki H, Wang KC. Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease. Neurobiol Aging. 2004;25(5):663–74.

    Article  CAS  PubMed  Google Scholar 

  126. Kovacs GG, Ferrer I, Grinberg LT, Alafuzoff I, Attems J, Budka H, et al. Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy. Acta Neuropathol. 2016;131(1):87–102.

    Article  CAS  PubMed  Google Scholar 

  127. Kovacs GG, Robinson JL, Xie SX, Lee EB, Grossman M, Wolk DA, et al. Evaluating the patterns of aging-related tau astrogliopathy unravels novel insights into brain aging and neurodegenerative diseases. J Neuropathol Exp Neurol. 2017;76(4):270–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Lian H, Yang L, Cole A, Sun L, Chiang AC, Fowler SW, et al. NFkappaB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer’s disease. Neuron. 2015;85(1):101–15.

    Article  CAS  PubMed  Google Scholar 

  129. Kaltschmidt B, Uherek M, Volk B, Baeuerle PA, Kaltschmidt C. Transcription factor NF-kappaB is activated in primary neurons by amyloid beta peptides and in neurons surrounding early plaques from patients with Alzheimer disease. Proc Natl Acad Sci U S A. 1997;94(6):2642–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016;352(6286):712–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, Giffard RG, et al. Genomic analysis of reactive astrogliosis. J Neurosci. 2012;32(18):6391–410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541(7638):481–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA

    Gilbert Gallardo & David M. Holtzman

  2. Hope Center for Neurological Disorders, Washington University, St. Louis, MO, USA

    Gilbert Gallardo & David M. Holtzman

  3. Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO, USA

    David M. Holtzman

Authors
  1. Gilbert Gallardo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David M. Holtzman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David M. Holtzman .

Editor information

Editors and Affiliations

  1. Department of Life Sciences, Gakushuin University, Tokyo, Japan

    Akihiko Takashima

  2. Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA

    Benjamin Wolozin

  3. University of Lille, INSERM, CHU-Lille, Alzheimer & Tauopathies, LabEx DISTALZ, Lille, France

    Luc Buee

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Gallardo, G., Holtzman, D.M. (2019). Amyloid-β and Tau at the Crossroads of Alzheimer’s Disease. In: Takashima, A., Wolozin, B., Buee, L. (eds) Tau Biology. Advances in Experimental Medicine and Biology, vol 1184. Springer, Singapore. https://doi.org/10.1007/978-981-32-9358-8_16

Download citation

Publish with us

Policies and ethics

Search

Navigation