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The existence of Aβ strains and their potential for driving phenotypic heterogeneity in Alzheimer’s disease

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Abstract

Reminiscent of the human prion diseases, there is considerable clinical and pathological variability in Alzheimer’s disease, the most common human neurodegenerative condition. As in prion disorders, protein misfolding and aggregation is a hallmark feature of Alzheimer’s disease, where the initiating event is thought to be the self-assembly of Aβ peptide into aggregates that deposit in the central nervous system. Emerging evidence suggests that Aβ, similar to the prion protein, can polymerize into a conformationally diverse spectrum of aggregate strains both in vitro and within the brain. Moreover, certain types of Aβ aggregates exhibit key hallmarks of prion strains including divergent biochemical attributes and the ability to induce distinct pathological phenotypes when intracerebrally injected into mouse models. In this review, we discuss the evidence demonstrating that Aβ can assemble into distinct strains of aggregates and how such strains may be primary drivers of the phenotypic heterogeneity in Alzheimer’s disease.

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References

  1. Ahmed M, Davis J, Aucoin D, Sato T, Ahuja S, Aimoto S et al (2010) Structural conversion of neurotoxic amyloid-beta(1–42) oligomers to fibrils. Nat Struct Mol Biol 17:561–567. https://doi.org/10.1038/nsmb.1799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Aizenstein HJ, Nebes RD, Saxton JA, Price JC, Mathis CA, Tsopelas ND et al (2008) Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol 65:1509–1517. https://doi.org/10.1001/archneur.65.11.1509

    Article  PubMed  PubMed Central  Google Scholar 

  3. Aslund A, Sigurdson CJ, Klingstedt T, Grathwohl S, Bolmont T, Dickstein DL et al (2009) Novel pentameric thiophene derivatives for in vitro and in vivo optical imaging of a plethora of protein aggregates in cerebral amyloidoses. ACS Chem Biol 4:673–684. https://doi.org/10.1021/cb900112v

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Attems J, Jellinger KA, Lintner F (2005) Alzheimer's disease pathology influences severity and topographical distribution of cerebral amyloid angiopathy. Acta Neuropathol 110:222–231. https://doi.org/10.1007/s00401-005-1064-y

    Article  PubMed  Google Scholar 

  5. Atwood CS, Scarpa RC, Huang X, Moir RD, Jones WD, Fairlie DP et al (2000) Characterization of copper interactions with alzheimer amyloid beta peptides: identification of an attomolar-affinity copper binding site on amyloid beta1-42. J Neurochem 75:1219–1233. https://doi.org/10.1046/j.1471-4159.2000.0751219.x

    Article  CAS  PubMed  Google Scholar 

  6. Bachhuber T, Katzmarski N, McCarter JF, Loreth D, Tahirovic S, Kamp F et al (2015) Inhibition of amyloid-beta plaque formation by alpha-synuclein. Nat Med 21:802–807. https://doi.org/10.1038/nm.3885

    Article  CAS  PubMed  Google Scholar 

  7. Banerjee G, Adams ME, Jaunmuktane Z, Alistair Lammie G, Turner B, Wani M et al (2019) Early onset cerebral amyloid angiopathy following childhood exposure to cadaveric dura. Ann Neurol 85:284–290. https://doi.org/10.1002/ana.25407

    Article  PubMed  PubMed Central  Google Scholar 

  8. Bassil F, Brown HJ, Pattabhiraman S, Iwasyk JE, Maghames CM, Meymand ES et al (2020) Amyloid-beta (Abeta) plaques promote seeding and spreading of alpha-synuclein and tau in a mouse model of Lewy body disorders with Abeta pathology. Neuron 105(260–275):e266. https://doi.org/10.1016/j.neuron.2019.10.010

    Article  CAS  Google Scholar 

  9. Benilova I, Karran E, De Strooper B (2012) The toxic Abeta oligomer and Alzheimer's disease: an emperor in need of clothes. Nat Neurosci 15:349–357. https://doi.org/10.1038/nn.3028

    Article  CAS  PubMed  Google Scholar 

  10. Berry DB, Lu D, Geva M, Watts JC, Bhardwaj S, Oehler A et al (2013) Drug resistance confounding prion therapeutics. Proc Natl Acad Sci USA 110:E4160–4169. https://doi.org/10.1073/pnas.1317164110

    Article  PubMed  PubMed Central  Google Scholar 

  11. Bertini I, Gonnelli L, Luchinat C, Mao J, Nesi A (2011) A new structural model of Abeta40 fibrils. J Am Chem Soc 133:16013–16022. https://doi.org/10.1021/ja2035859

    Article  CAS  PubMed  Google Scholar 

  12. Bolmont T, Clavaguera F, Meyer-Luehmann M, Herzig MC, Radde R, Staufenbiel M et al (2007) 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 171:2012–2020. https://doi.org/10.2353/ajpath.2007.070403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112:389–404. https://doi.org/10.1007/s00401-006-0127-z

    Article  PubMed  PubMed Central  Google Scholar 

  14. Bugiani O, Giaccone G, Rossi G, Mangieri M, Capobianco R, Morbin M et al (2010) Hereditary cerebral hemorrhage with amyloidosis associated with the E693K mutation of APP. Arch Neurol 67:987–995. https://doi.org/10.1001/archneurol.2010.178

    Article  PubMed  Google Scholar 

  15. Burgold S, Bittner T, Dorostkar MM, Kieser D, Fuhrmann M, Mitteregger G et al (2011) In vivo multiphoton imaging reveals gradual growth of newborn amyloid plaques over weeks. Acta Neuropathol 121:327–335. https://doi.org/10.1007/s00401-010-0787-6

    Article  PubMed  Google Scholar 

  16. Cali I, Cohen ML, Hasmallyi US, Parchi P, Giaccone G, Collins SJ et al (2018) Iatrogenic Creutzfeldt-Jakob disease with Amyloid-beta pathology: an international study. Acta Neuropathol Commun 6:5. https://doi.org/10.1186/s40478-017-0503-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW et al (2011) Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance. Sci Transl Med 3:89ra57. https://doi.org/10.1126/scitranslmed.3002156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cendrowska U, Silva PJ, Ait-Bouziad N, Muller M, Guven ZP, Vieweg S et al (2020) Unraveling the complexity of amyloid polymorphism using gold nanoparticles and cryo-EM. Proc Natl Acad Sci USA 117:6866–6874. https://doi.org/10.1073/pnas.1916176117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Clark CM, Pontecorvo MJ, Beach TG, Bedell BJ, Coleman RE, Doraiswamy PM et al (2012) Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-beta plaques: a prospective cohort study. Lancet Neurol 11:669–678. https://doi.org/10.1016/S1474-4422(12)70142-4

    Article  CAS  PubMed  Google Scholar 

  20. Clavaguera F, Akatsu H, Fraser G, Crowther RA, Frank S, Hench J et al (2013) Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci USA 110:9535–9540. https://doi.org/10.1073/pnas.1301175110

    Article  PubMed  PubMed Central  Google Scholar 

  21. Cloe AL, Orgel JP, Sachleben JR, Tycko R, Meredith SC (2011) The Japanese mutant Abeta (DeltaE22-Abeta(1–39)) forms fibrils instantaneously, with low-thioflavin T fluorescence: seeding of wild-type Abeta(1–40) into atypical fibrils by DeltaE22-Abeta(1–39). Biochemistry 50:2026–2039. https://doi.org/10.1021/bi1016217

    Article  CAS  PubMed  Google Scholar 

  22. Cohen ML, Kim C, Haldiman T, ElHag M, Mehndiratta P, Pichet T et al (2015) Rapidly progressive Alzheimer's disease features distinct structures of amyloid-beta. Brain 138:1009–1022. https://doi.org/10.1093/brain/awv006

    Article  PubMed  PubMed Central  Google Scholar 

  23. Colletier JP, Laganowsky A, Landau M, Zhao M, Soriaga AB, Goldschmidt L et al (2011) Molecular basis for amyloid-beta polymorphism. Proc Natl Acad Sci USA 108:16938–16943. https://doi.org/10.1073/pnas.1112600108

    Article  PubMed  PubMed Central  Google Scholar 

  24. Collinge J, Clarke AR (2007) A general model of prion strains and their pathogenicity. Science 318:930–936. https://doi.org/10.1126/science.1138718

    Article  CAS  PubMed  Google Scholar 

  25. Colvin MT, Silvers R, Ni QZ, Can TV, Sergeyev I, Rosay M et al (2016) Atomic resolution structure of monomorphic Abeta42 amyloid fibrils. J Am Chem Soc 138:9663–9674. https://doi.org/10.1021/jacs.6b05129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Condello C, Lemmin T, Stohr J, Nick M, Wu Y, Maxwell AM et al (2018) Structural heterogeneity and intersubject variability of Abeta in familial and sporadic Alzheimer's disease. Proc Natl Acad Sci USA 115:E782–E791. https://doi.org/10.1073/pnas.1714966115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Condello C, Schain A, Grutzendler J (2011) Multicolor time-stamp reveals the dynamics and toxicity of amyloid deposition. Sci Rep 1:19. https://doi.org/10.1038/srep00019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Condello C, Stoehr J (2018) Abeta propagation and strains: Implications for the phenotypic diversity in Alzheimer's disease. Neurobiol Dis 109:191–200. https://doi.org/10.1016/j.nbd.2017.03.014

    Article  PubMed  Google Scholar 

  29. Cras P, van Harskamp F, Hendriks L, Ceuterick C, van Duijn CM, Stefanko SZ et al (1998) Presenile Alzheimer dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692Ala–>Gly mutation. Acta Neuropathol 96:253–260. https://doi.org/10.1007/s004010050892

    Article  CAS  PubMed  Google Scholar 

  30. Crook R, Verkkoniemi A, Perez-Tur J, Mehta N, Baker M, Houlden H et al (1998) A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nat Med 4:452–455. https://doi.org/10.1038/nm0498-452

    Article  CAS  PubMed  Google Scholar 

  31. Cukalevski R, Yang X, Meisl G, Weininger U, Bernfur K, Frohm B et al (2015) The Abeta40 and Abeta42 peptides self-assemble into separate homomolecular fibrils in binary mixtures but cross-react during primary nucleation. Chem Sci 6:4215–4233. https://doi.org/10.1039/c4sc02517b

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. DaRocha-Souto B, Scotton TC, Coma M, Serrano-Pozo A, Hashimoto T, Sereno L et al (2011) Brain oligomeric beta-amyloid but not total amyloid plaque burden correlates with neuronal loss and astrocyte inflammatory response in amyloid precursor protein/tau transgenic mice. J Neuropathol Exp Neurol 70:360–376. https://doi.org/10.1097/NEN.0b013e318217a118

    Article  CAS  PubMed  Google Scholar 

  33. De Strooper B, Karran E (2016) The cellular phase of Alzheimer's disease. Cell 164:603–615. https://doi.org/10.1016/j.cell.2015.12.056

    Article  CAS  PubMed  Google Scholar 

  34. Dean DN, Das PK, Rana P, Burg F, Levites Y, Morgan SE et al (2017) Strain-specific fibril propagation by an Abeta dodecamer. Sci Rep 7:40787. https://doi.org/10.1038/srep40787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Dear AJ, Michaels TCT, Meisl G, Klenerman D, Wu S, Perrett S et al (2020) Kinetic diversity of amyloid oligomers. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.1922267117

    Article  PubMed  PubMed Central  Google Scholar 

  36. Degerman Gunnarsson M, Ingelsson M, Blennow K, Basun H, Lannfelt L, Kilander L (2016) High tau levels in cerebrospinal fluid predict nursing home placement and rapid progression in Alzheimer's disease. Alzheimer's Res Ther 8:22. https://doi.org/10.1186/s13195-016-0191-0

    Article  CAS  Google Scholar 

  37. Devanand DP, Michaels-Marston KS, Liu X, Pelton GH, Padilla M, Marder K et al (2000) Olfactory deficits in patients with mild cognitive impairment predict Alzheimer's disease at follow-up. Am J Psychiatry 157:1399–1405. https://doi.org/10.1176/appi.ajp.157.9.1399

    Article  CAS  PubMed  Google Scholar 

  38. Di Fede G, Catania M, Maderna E, Ghidoni R, Benussi L, Tonoli E et al (2018) Molecular subtypes of Alzheimer's disease. Sci Rep 8:3269. https://doi.org/10.1038/s41598-018-21641-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K et al (2014) Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. Lancet Neurol 13:614–629. https://doi.org/10.1016/S1474-4422(14)70090-0

    Article  PubMed  Google Scholar 

  40. Dujardin S, Commins C, Lathuiliere A, Beerepoot P, Fernandes AR, Kamath TV et al (2020) Tau molecular diversity contributes to clinical heterogeneity in Alzheimer's disease. Nat Med. https://doi.org/10.1038/s41591-020-0938-9

    Article  PubMed  Google Scholar 

  41. Duyckaerts C, Delatour B, Potier MC (2009) Classification and basic pathology of Alzheimer disease. Acta Neuropathol 118:5–36. https://doi.org/10.1007/s00401-009-0532-1

    Article  CAS  PubMed  Google Scholar 

  42. Duyckaerts C, Sazdovitch V, Ando K, Seilhean D, Privat N, Yilmaz Z et al (2018) Neuropathology of iatrogenic Creutzfeldt-Jakob disease and immunoassay of French cadaver-sourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Abeta pathology. Acta Neuropathol 135:201–212. https://doi.org/10.1007/s00401-017-1791-x

    Article  CAS  PubMed  Google Scholar 

  43. Eisele YS, Bolmont T, Heikenwalder M, Langer F, Jacobson LH, Yan ZX et al (2009) Induction of cerebral beta-amyloidosis: intracerebral versus systemic Abeta inoculation. Proc Natl Acad Sci USA 106:12926–12931. https://doi.org/10.1073/pnas.0903200106

    Article  PubMed  PubMed Central  Google Scholar 

  44. Eisele YS, Obermuller U, Heilbronner G, Baumann F, Kaeser SA, Wolburg H et al (2010) Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis. Science 330:980–982. https://doi.org/10.1126/science.1194516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Elkins MR, Wang T, Nick M, Jo H, Lemmin T, Prusiner SB et al (2016) Structural polymorphism of Alzheimer's beta-amyloid fibrils as controlled by an E22 Switch: a solid-state NMR study. J Am Chem Soc 138:9840–9852. https://doi.org/10.1021/jacs.6b03715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Esparza TJ, Zhao H, Cirrito JR, Cairns NJ, Bateman RJ, Holtzman DM et al (2013) Amyloid-beta oligomerization in Alzheimer dementia versus high-pathology controls. Ann Neurol 73:104–119. https://doi.org/10.1002/ana.23748

    Article  CAS  PubMed  Google Scholar 

  47. Falcon B, Zhang W, Murzin AG, Murshudov G, Garringer HJ, Vidal R et al (2018) Structures of filaments from Pick's disease reveal a novel tau protein fold. Nature 561:137–140. https://doi.org/10.1038/s41586-018-0454-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Falcon B, Zhang W, Schweighauser M, Murzin AG, Vidal R, Garringer HJ et al (2018) Tau filaments from multiple cases of sporadic and inherited Alzheimer's disease adopt a common fold. Acta Neuropathol 136:699–708. https://doi.org/10.1007/s00401-018-1914-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Falcon B, Zivanov J, Zhang W, Murzin AG, Garringer HJ, Vidal R et al (2019) Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Nature 568:420–423. https://doi.org/10.1038/s41586-019-1026-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ferreira D, Nordberg A, Westman E (2020) Biological subtypes of Alzheimer disease: a systematic review and meta-analysis. Neurology 94:436–448. https://doi.org/10.1212/WNL.0000000000009058

    Article  PubMed  PubMed Central  Google Scholar 

  51. Fitzpatrick AWP, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ et al (2017) Cryo-EM structures of tau filaments from Alzheimer's disease. Nature 547:185–190. https://doi.org/10.1038/nature23002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Frontzek K, Lutz MI, Aguzzi A, Kovacs GG, Budka H (2016) Amyloid-beta pathology and cerebral amyloid angiopathy are frequent in iatrogenic Creutzfeldt-Jakob disease after dural grafting. Swiss Med Wkly 146:w14287. https://doi.org/10.4414/smw.2016.14287

    Article  CAS  PubMed  Google Scholar 

  53. Ghaemmaghami S, Ahn M, Lessard P, Giles K, Legname G, DeArmond SJ et al (2009) Continuous quinacrine treatment results in the formation of drug-resistant prions. PLoS Pathog 5:e1000673

    Article  Google Scholar 

  54. Giaccone G, Maderna E, Marucci G, Catania M, Erbetta A, Chiapparini L et al (2019) Iatrogenic early onset cerebral amyloid angiopathy 30 years after cerebral trauma with neurosurgery: vascular amyloid deposits are made up of both Abeta40 and Abeta42. Acta Neuropathol Commun 7:70. https://doi.org/10.1186/s40478-019-0719-1

    Article  PubMed  PubMed Central  Google Scholar 

  55. Gibbons GS, Lee VMY, Trojanowski JQ (2019) Mechanisms of cell-to-cell transmission of pathological tau: a review. JAMA Neurol 76:101–108. https://doi.org/10.1001/jamaneurol.2018.2505

    Article  PubMed  PubMed Central  Google Scholar 

  56. Goldsbury C, Frey P, Olivieri V, Aebi U, Muller SA (2005) Multiple assembly pathways underlie amyloid-beta fibril polymorphisms. J Mol Biol 352:282–298. https://doi.org/10.1016/j.jmb.2005.07.029

    Article  CAS  PubMed  Google Scholar 

  57. Gomperts SN, Locascio JJ, Rentz D, Santarlasci A, Marquie M, Johnson KA et al (2013) Amyloid is linked to cognitive decline in patients with Parkinson disease without dementia. Neurology 80:85–91. https://doi.org/10.1212/WNL.0b013e31827b1a07

    Article  PubMed  PubMed Central  Google Scholar 

  58. Gotz J, Chen F, van Dorpe J, Nitsch RM (2001) Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293:1491–1495. https://doi.org/10.1126/science.1062097

    Article  CAS  PubMed  Google Scholar 

  59. Grabowski TJ, Cho HS, Vonsattel JP, Rebeck GW, Greenberg SM (2001) Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. Ann Neurol 49:697–705. https://doi.org/10.1002/ana.1009

    Article  CAS  PubMed  Google Scholar 

  60. Gregory GC, Halliday GM (2005) What is the dominant Abeta species in human brain tissue? A review. Neurotox Res 7:29–41. https://doi.org/10.1007/BF03033774

    Article  CAS  PubMed  Google Scholar 

  61. Gremer L, Scholzel D, Schenk C, Reinartz E, Labahn J, Ravelli RBG et al (2017) Fibril structure of amyloid-beta(1–42) by cryo-electron microscopy. Science 358:116–119. https://doi.org/10.1126/science.aao2825

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gu L, Guo Z (2013) Alzheimer's Abeta42 and Abeta40 peptides form interlaced amyloid fibrils. J Neurochem 126:305–311. https://doi.org/10.1111/jnc.12202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Guo JL, Narasimhan S, Changolkar L, He Z, Stieber A, Zhang B et al (2016) Unique pathological tau conformers from Alzheimer's brains transmit tau pathology in nontransgenic mice. J Exp Med 213:2635–2654. https://doi.org/10.1084/jem.20160833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol 8:101–112. https://doi.org/10.1038/nrm2101

    Article  CAS  PubMed  Google Scholar 

  65. Hamaguchi T, Eisele YS, Varvel NH, Lamb BT, Walker LC, Jucker M (2012) The presence of Aβ seeds, and not age per se, is critical to the initiation of Aβ deposition in the brain. Acta Neuropathol 123:31–37. https://doi.org/10.1007/s00401-011-0912-1

    Article  CAS  PubMed  Google Scholar 

  66. Hamaguchi T, Taniguchi Y, Sakai K, Kitamoto T, Takao M, Murayama S et al (2016) Significant association of cadaveric dura mater grafting with subpial Abeta deposition and meningeal amyloid angiopathy. Acta Neuropathol 132:313–315. https://doi.org/10.1007/s00401-016-1588-3

    Article  PubMed  Google Scholar 

  67. Hao YN, Lu QX, Zhai YH, Wang HY, Wu MN, Hu MM et al (2018) Cerebral inoculation of human A53T alpha-synuclein reduces spatial memory decline and amyloid-beta aggregation in APP/PS1 transgenic mice of Alzheimer's disease. Brain Res Bull 143:116–122. https://doi.org/10.1016/j.brainresbull.2018.10.003

    Article  CAS  PubMed  Google Scholar 

  68. Hasegawa K, Yamaguchi I, Omata S, Gejyo F, Naiki H (1999) Interaction between A beta(1–42) and A beta(1–40) in Alzheimer's beta-amyloid fibril formation in vitro. Biochemistry 38:15514–15521. https://doi.org/10.1021/bi991161m

    Article  CAS  PubMed  Google Scholar 

  69. Hatami A, Albay R 3rd, Monjazeb S, Milton S, Glabe C (2014) Monoclonal antibodies against Abeta42 fibrils distinguish multiple aggregation state polymorphisms in vitro and in Alzheimer disease brain. J Biol Chem 289:32131–32143. https://doi.org/10.1074/jbc.M114.594846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Hatami A, Monjazeb S, Milton S, Glabe CG (2017) Familial Alzheimer's disease mutations within the amyloid precursor protein alter the aggregation and conformation of the amyloid-beta peptide. J Biol Chem 292:3172–3185. https://doi.org/10.1074/jbc.M116.755264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. He Z, Guo JL, McBride JD, Narasimhan S, Kim H, Changolkar L et al (2018) Amyloid-beta plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med 24:29–38. https://doi.org/10.1038/nm.4443

    Article  CAS  PubMed  Google Scholar 

  72. Heilbronner G, Eisele YS, Langer F, Kaeser SA, Novotny R, Nagarathinam A et al (2013) Seeded strain-like transmission of beta-amyloid morphotypes in APP transgenic mice. EMBO Rep 14:1017–1022. https://doi.org/10.1038/embor.2013.137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hendriks L, van Duijn CM, Cras P, Cruts M, Van Hul W, van Harskamp F et al (1992) Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the beta-amyloid precursor protein gene. Nat Genet 1:218–221. https://doi.org/10.1038/ng0692-218

    Article  CAS  PubMed  Google Scholar 

  74. Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL et al (2015) Neuroinflammation in Alzheimer's disease. Lancet Neurol 14:388–405. https://doi.org/10.1016/S1474-4422(15)70016-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Herrup K (2015) The case for rejecting the amyloid cascade hypothesis. Nat Neurosci 18:794–799. https://doi.org/10.1038/nn.4017

    Article  CAS  PubMed  Google Scholar 

  76. Herve D, Porche M, Cabrejo L, Guidoux C, Tournier-Lasserve E, Nicolas G et al (2018) Fatal Abeta cerebral amyloid angiopathy 4 decades after a dural graft at the age of 2 years. Acta Neuropathol. https://doi.org/10.1007/s00401-018-1828-9

    Article  PubMed  Google Scholar 

  77. Holec SAM, Woerman AL (2020) Evidence of distinct alpha-synuclein strains underlying disease heterogeneity. Acta Neuropathol. https://doi.org/10.1007/s00401-020-02163-5

    Article  PubMed  Google Scholar 

  78. Houlden H, Baker M, McGowan E, Lewis P, Hutton M, Crook R et al (2000) Variant Alzheimer's disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations. Ann Neurol 48:806–808

    Article  CAS  Google Scholar 

  79. Howard R, Liu KY (2020) Questions EMERGE as Biogen claims aducanumab turnaround. Nat Rev Neurol 16:63–64. https://doi.org/10.1038/s41582-019-0295-9

    Article  PubMed  Google Scholar 

  80. Ingelsson M, Fukumoto H, Newell KL, Growdon JH, Hedley-Whyte ET, Frosch MP et al (2004) Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology 62:925–931. https://doi.org/10.1212/01.wnl.0000115115.98960.37

    Article  CAS  PubMed  Google Scholar 

  81. Ironside JW, Head MW (2004) Neuropathology and molecular biology of variant Creutzfeldt-Jakob disease. Curr Top Microbiol Immunol 284:133–159. https://doi.org/10.1007/978-3-662-08441-0_6

    Article  CAS  PubMed  Google Scholar 

  82. Jaunmuktane Z, Mead S, Ellis M, Wadsworth JD, Nicoll AJ, Kenny J et al (2015) Evidence for human transmission of amyloid-beta pathology and cerebral amyloid angiopathy. Nature 525:247–250. https://doi.org/10.1038/nature15369

    Article  CAS  PubMed  Google Scholar 

  83. Jaunmuktane Z, Quaegebeur A, Taipa R, Viana-Baptista M, Barbosa R, Koriath C et al (2018) Evidence of amyloid-beta cerebral amyloid angiopathy transmission through neurosurgery. Acta Neuropathol. https://doi.org/10.1007/s00401-018-1822-2

    Article  PubMed  PubMed Central  Google Scholar 

  84. Jeibouei S, Akbari ME, Kalbasi A, Aref AR, Ajoudanian M, Rezvani A et al (2019) Personalized medicine in breast cancer: pharmacogenomics approaches. Pharmgenomics Pers Med 12:59–73. https://doi.org/10.2147/PGPM.S167886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Johansson AS, Berglind-Dehlin F, Karlsson G, Edwards K, Gellerfors P, Lannfelt L (2006) Physiochemical characterization of the Alzheimer's disease-related peptides A beta 1–42Arctic and A beta 1–42wt. FEBS J 273:2618–2630. https://doi.org/10.1111/j.1742-4658.2006.05263.x

    Article  CAS  PubMed  Google Scholar 

  86. Josephs KA, Murray ME, Whitwell JL, Parisi JE, Petrucelli L, Jack CR et al (2014) Staging TDP-43 pathology in Alzheimer's disease. Acta Neuropathol 127:441–450. https://doi.org/10.1007/s00401-013-1211-9

    Article  CAS  PubMed  Google Scholar 

  87. Jucker M, Walker LC (2018) Propagation and spread of pathogenic protein assemblies in neurodegenerative diseases. Nat Neurosci 21:1341–1349. https://doi.org/10.1038/s41593-018-0238-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Jucker M, Walker LC (2013) Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501:45–51. https://doi.org/10.1038/nature12481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Kalimo H, Lalowski M, Bogdanovic N, Philipson O, Bird TD, Nochlin D et al (2013) The Arctic AbetaPP mutation leads to Alzheimer's disease pathology with highly variable topographic deposition of differentially truncated Abeta. Acta Neuropathol Commun 1:60. https://doi.org/10.1186/2051-5960-1-60

    Article  PubMed  PubMed Central  Google Scholar 

  90. Kallhoff V, Peethumnongsin E, Zheng H (2007) Lack of alpha-synuclein increases amyloid plaque accumulation in a transgenic mouse model of Alzheimer's disease. Mol Neurodegener 2:6. https://doi.org/10.1186/1750-1326-2-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Karran E, De Strooper B (2016) The amyloid cascade hypothesis: are we poised for success or failure? J Neurochem 139(Suppl 2):237–252. https://doi.org/10.1111/jnc.13632

    Article  CAS  PubMed  Google Scholar 

  92. Katzmarski N, Ziegler-Waldkirch S, Scheffler N, Witt C, Abou-Ajram C, Nuscher B et al (2020) Abeta oligomers trigger and accelerate Abeta seeding. Brain Pathol 30:36–45. https://doi.org/10.1111/bpa.12734

    Article  CAS  PubMed  Google Scholar 

  93. Kaufman SK, Sanders DW, Thomas TL, Ruchinskas AJ, Vaquer-Alicea J, Sharma AM et al (2016) Tau prion strains dictate patterns of cell pathology, progression rate, and regional vulnerability in vivo. Neuron 92:796–812. https://doi.org/10.1016/j.neuron.2016.09.055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kim T, Vidal GS, Djurisic M, William CM, Birnbaum ME, Garcia KC et al (2013) Human LilrB2 is a beta-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer's model. Science 341:1399–1404. https://doi.org/10.1126/science.1242077

    Article  CAS  PubMed  Google Scholar 

  95. Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP et al (2004) Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol 55:306–319. https://doi.org/10.1002/ana.20009

    Article  CAS  PubMed  Google Scholar 

  96. Klunk WE, Lopresti BJ, Ikonomovic MD, Lefterov IM, Koldamova RP, Abrahamson EE et al (2005) Binding of the positron emission tomography tracer Pittsburgh compound-B reflects the amount of amyloid-beta in Alzheimer's disease brain but not in transgenic mouse brain. J Neurosci 25:10598–10606. https://doi.org/10.1523/JNEUROSCI.2990-05.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kodali R, Williams AD, Chemuru S, Wetzel R (2010) Abeta(1–40) forms five distinct amyloid structures whose beta-sheet contents and fibril stabilities are correlated. J Mol Biol 401:503–517. https://doi.org/10.1016/j.jmb.2010.06.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kollmer M, Close W, Funk L, Rasmussen J, Bsoul A, Schierhorn A et al (2019) Cryo-EM structure and polymorphism of Abeta amyloid fibrils purified from Alzheimer's brain tissue. Nat Commun 10:4760. https://doi.org/10.1038/s41467-019-12683-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Kotzbauer PT, Trojanowsk JQ, Lee VM (2001) Lewy body pathology in Alzheimer's disease. J Mol Neurosci 17:225–232. https://doi.org/10.1385/jmn:17:2:225

    Article  CAS  PubMed  Google Scholar 

  100. Kumar A, Pate KM, Moss MA, Dean DN, Rangachari V (2014) Self-propagative replication of Abeta oligomers suggests potential transmissibility in Alzheimer disease. PLoS ONE 9:e111492. https://doi.org/10.1371/journal.pone.0111492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Kumar DK, Choi SH, Washicosky KJ, Eimer WA, Tucker S, Ghofrani J et al (2016) Amyloid-beta peptide protects against microbial infection in mouse and worm models of Alzheimer's disease. Sci Transl Med 8:340ra372. https://doi.org/10.1126/scitranslmed.aaf1059

    Article  CAS  Google Scholar 

  102. Kumar-Singh S, Cras P, Wang R, Kros JM, van Swieten J, Lubke U et al (2002) Dense-core senile plaques in the Flemish variant of Alzheimer's disease are vasocentric. Am J Pathol 161:507–520. https://doi.org/10.1016/S0002-9440(10)64207-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Kummer MP, Heneka MT (2014) Truncated and modified amyloid-beta species. Alzheimer's Res Ther 6:28. https://doi.org/10.1186/alzrt258

    Article  Google Scholar 

  104. Lam B, Masellis M, Freedman M, Stuss DT, Black SE (2013) Clinical, imaging, and pathological heterogeneity of the Alzheimer's disease syndrome. Alzheimer's Res Ther 5:1. https://doi.org/10.1186/alzrt155

    Article  Google Scholar 

  105. Landau SM, Horng A, Fero A, Jagust WJ, Alzheimer's Disease Neuroimaging I (2016) Amyloid negativity in patients with clinically diagnosed Alzheimer disease and MCI. Neurology 86:1377–1385. https://doi.org/10.1212/WNL.0000000000002576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Lau A, So RWL, Lau HHC, Sang JC, Ruiz-Riquelme A, Fleck SC et al (2020) Alpha-Synuclein strains target distinct brain regions and cell types. Nat Neurosci 23:21–31. https://doi.org/10.1038/s41593-019-0541-x

    Article  CAS  Google Scholar 

  107. Lau HHC, Lau A, Watts JC (2018) Discriminating strains of self-propagating protein aggregates using a conformational stability assay. Methods Mol Biol 1777:339–354. https://doi.org/10.1007/978-1-4939-7811-3_22

    Article  CAS  PubMed  Google Scholar 

  108. Lauren J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature 457:1128–1132. https://doi.org/10.1038/nature07761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Le TV, Crook R, Hardy J, Dickson DW (2001) Cotton wool plaques in non-familial late-onset Alzheimer disease. J Neuropathol Exp Neurol 60:1051–1061. https://doi.org/10.1093/jnen/60.11.1051

    Article  CAS  PubMed  Google Scholar 

  110. Lee SE, Rabinovici GD, Mayo MC, Wilson SM, Seeley WW, DeArmond SJ et al (2011) Clinicopathological correlations in corticobasal degeneration. Ann Neurol 70:327–340. https://doi.org/10.1002/ana.22424

    Article  PubMed  PubMed Central  Google Scholar 

  111. Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A et al (2006) A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440:352–357. https://doi.org/10.1038/nature04533

    Article  CAS  PubMed  Google Scholar 

  112. Levine H 3rd, Walker LC (2010) Molecular polymorphism of Abeta in Alzheimer's disease. Neurobiol Aging 31:542–548. https://doi.org/10.1016/j.neurobiolaging.2008.05.026

    Article  CAS  PubMed  Google Scholar 

  113. Levy E, Carman MD, Fernandez-Madrid IJ, Power MD, Lieberburg I, van Duinen SG et al (1990) Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248:1124–1126. https://doi.org/10.1126/science.2111584

    Article  CAS  PubMed  Google Scholar 

  114. Li J, Browning S, Mahal SP, Oelschlegel AM, Weissmann C (2010) Darwinian evolution of prions in cell culture. Science 327:869–872. https://doi.org/10.1126/science.1183218

    Article  CAS  PubMed  Google Scholar 

  115. Liu J, Costantino I, Venugopalan N, Fischetti RF, Hyman BT, Frosch MP et al (2016) Amyloid structure exhibits polymorphism on multiple length scales in human brain tissue. Sci Rep 6:33079. https://doi.org/10.1038/srep33079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Lorenzo A, Yuan M, Zhang Z, Paganetti PA, Sturchler-Pierrat C, Staufenbiel M et al (2000) Amyloid beta interacts with the amyloid precursor protein: a potential toxic mechanism in Alzheimer's disease. Nat Neurosci 3:460–464. https://doi.org/10.1038/74833

    Article  CAS  PubMed  Google Scholar 

  117. Lu JX, Qiang W, Yau WM, Schwieters CD, Meredith SC, Tycko R (2013) Molecular structure of beta-amyloid fibrils in Alzheimer's disease brain tissue. Cell 154:1257–1268. https://doi.org/10.1016/j.cell.2013.08.035

    Article  CAS  PubMed  Google Scholar 

  118. Luhrs T, Ritter C, Adrian M, Riek-Loher D, Bohrmann B, Dobeli H et al (2005) 3D structure of Alzheimer's amyloid-beta(1–42) fibrils. Proc Natl Acad Sci USA 102:17342–17347. https://doi.org/10.1073/pnas.0506723102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Makowski L (2019) The structural basis of amyloid strains in Alzheimer’s disease. ACS Biomater Sci Eng. https://doi.org/10.1021/acsbiomaterials.9b01302

    Article  PubMed  Google Scholar 

  120. Masliah E, Rockenstein E, Veinbergs I, Sagara Y, Mallory M, Hashimoto M et al (2001) 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 98:12245–12250. https://doi.org/10.1073/pnas.211412398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Meinhardt J, Sachse C, Hortschansky P, Grigorieff N, Fandrich M (2009) Abeta(1–40) fibril polymorphism implies diverse interaction patterns in amyloid fibrils. J Mol Biol 386:869–877. https://doi.org/10.1016/j.jmb.2008.11.005

    Article  CAS  PubMed  Google Scholar 

  122. Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C, Kilger E et al (2006) Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 313:1781–1784. https://doi.org/10.1126/science.1131864

    Article  CAS  PubMed  Google Scholar 

  123. Meyer-Luehmann M, Spires-Jones TL, Prada C, Garcia-Alloza M, de Calignon A, Rozkalne A et al (2008) Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease. Nature 451:720–724. https://doi.org/10.1038/nature06616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Dickson DW et al (2012) National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach. Acta Neuropathol 123:1–11. https://doi.org/10.1007/s00401-011-0910-3

    Article  CAS  PubMed  Google Scholar 

  125. Morales R, Duran-Aniotz C, Castilla J, Estrada LD, Soto C (2012) De novo induction of amyloid-β deposition in vivo. Mol Psychiatry. https://doi.org/10.1038/mp.2011.120

    Article  PubMed  Google Scholar 

  126. Moro ML, Giaccone G, Lombardi R, Indaco A, Uggetti A, Morbin M et al (2012) APP mutations in the Abeta coding region are associated with abundant cerebral deposition of Abeta38. Acta Neuropathol 124:809–821. https://doi.org/10.1007/s00401-012-1061-x

    Article  CAS  PubMed  Google Scholar 

  127. Narasimhan S, Guo JL, Changolkar L, Stieber A, McBride JD, Silva LV et al (2017) Pathological tau strains from human brains recapitulate the diversity of tauopathies in nontransgenic mouse brain. J Neurosci 37:11406–11423. https://doi.org/10.1523/JNEUROSCI.1230-17.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Naslund J, Haroutunian V, Mohs R, Davis KL, Davies P, Greengard P et al (2000) Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA 283:1571–1577. https://doi.org/10.1001/jama.283.12.1571

    Article  CAS  PubMed  Google Scholar 

  129. Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C et al (2001) The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation. Nat Neurosci 4:887–893. https://doi.org/10.1038/nn0901-887

    Article  CAS  PubMed  Google Scholar 

  130. Nilsson KP, Aslund A, Berg I, Nystrom S, Konradsson P, Herland A, Inganas O et al (2007) Imaging distinct conformational states of amyloid-beta fibrils in Alzheimer's disease using novel luminescent probes. ACS Chem Biol 2:553–560. https://doi.org/10.1021/cb700116u

    Article  CAS  PubMed  Google Scholar 

  131. Noble GP, Wang DW, Walsh DJ, Barone JR, Miller MB, Nishina KA et al (2015) A Structural and functional comparison between infectious and non-infectious autocatalytic recombinant PrP conformers. PLoS Pathog 11:e1005017. https://doi.org/10.1371/journal.ppat.1005017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Nystrom S, Psonka-Antonczyk KM, Ellingsen PG, Johansson LB, Reitan N, Handrick S et al (2013) Evidence for age-dependent in vivo conformational rearrangement within Abeta amyloid deposits. ACS Chem Biol 8:1128–1133. https://doi.org/10.1021/cb4000376

    Article  CAS  PubMed  Google Scholar 

  133. Obici L, Demarchi A, de Rosa G, Bellotti V, Marciano S, Donadei S et al (2005) A novel AbetaPP mutation exclusively associated with cerebral amyloid angiopathy. Ann Neurol 58:639–644. https://doi.org/10.1002/ana.20571

    Article  CAS  PubMed  Google Scholar 

  134. Ono K, Takahashi R, Ikeda T, Yamada M (2012) Cross-seeding effects of amyloid beta-protein and alpha-synuclein. J Neurochem 122:883–890. https://doi.org/10.1111/j.1471-4159.2012.07847.x

    Article  CAS  PubMed  Google Scholar 

  135. Ossenkoppele R, Schonhaut DR, Scholl M, Lockhart SN, Ayakta N, Baker SL et al (2016) Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease. Brain 139:1551–1567. https://doi.org/10.1093/brain/aww027

    Article  PubMed  PubMed Central  Google Scholar 

  136. Paravastu AK, Leapman RD, Yau WM, Tycko R (2008) Molecular structural basis for polymorphism in Alzheimer's beta-amyloid fibrils. Proc Natl Acad Sci USA 105:18349–18354. https://doi.org/10.1073/pnas.0806270105

    Article  PubMed  PubMed Central  Google Scholar 

  137. Paravastu AK, Qahwash I, Leapman RD, Meredith SC, Tycko R (2009) Seeded growth of beta-amyloid fibrils from Alzheimer's brain-derived fibrils produces a distinct fibril structure. Proc Natl Acad Sci USA 106:7443–7448. https://doi.org/10.1073/pnas.0812033106

    Article  PubMed  PubMed Central  Google Scholar 

  138. Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O et al (1999) Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 46:224–233

    Article  CAS  Google Scholar 

  139. Parchi P, Strammiello R, Notari S, Giese A, Langeveld JP, Ladogana A et al (2009) Incidence and spectrum of sporadic Creutzfeldt-Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification. Acta Neuropathol 118:659–671. https://doi.org/10.1007/s00401-009-0585-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Pauwels K, Williams TL, Morris KL, Jonckheere W, Vandersteen A, Kelly G et al (2012) Structural basis for increased toxicity of pathological abeta42:abeta40 ratios in Alzheimer disease. J Biol Chem 287:5650–5660. https://doi.org/10.1074/jbc.M111.264473

    Article  CAS  PubMed  Google Scholar 

  141. Perez-Nievas BG, Stein TD, Tai HC, Dols-Icardo O, Scotton TC, Barroeta-Espar I et al (2013) Dissecting phenotypic traits linked to human resilience to Alzheimer's pathology. Brain 136:2510–2526. https://doi.org/10.1093/brain/awt171

    Article  PubMed  PubMed Central  Google Scholar 

  142. Petkova AT, Leapman RD, Guo Z, Yau WM, Mattson MP, Tycko R (2005) Self-propagating, molecular-level polymorphism in Alzheimer's beta-amyloid fibrils. Science 307:262–265. https://doi.org/10.1126/science.1105850

    Article  CAS  PubMed  Google Scholar 

  143. Petkova AT, Yau WM, Tycko R (2006) Experimental constraints on quaternary structure in Alzheimer's beta-amyloid fibrils. Biochemistry 45:498–512. https://doi.org/10.1021/bi051952q

    Article  CAS  PubMed  Google Scholar 

  144. Piccini A, Russo C, Gliozzi A, Relini A, Vitali A, Borghi R et al (2005) beta-amyloid is different in normal aging and in Alzheimer disease. J Biol Chem 280:34186–34192. https://doi.org/10.1074/jbc.M501694200

    Article  CAS  PubMed  Google Scholar 

  145. Pirisinu L, Di Bari MA, D'Agostino C, Marcon S, Riccardi G, Poleggi A et al (2016) Gerstmann-Straussler-Scheinker disease subtypes efficiently transmit in bank voles as genuine prion diseases. Sci Rep 6:20443. https://doi.org/10.1038/srep20443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Polymenidou M, Stoeck K, Glatzel M, Vey M, Bellon A, Aguzzi A (2005) Coexistence of multiple PrPSc types in individuals with Creutzfeldt-Jakob disease. Lancet Neurol 4:805–814. https://doi.org/10.1016/S1474-4422(05)70225-8

    Article  CAS  PubMed  Google Scholar 

  147. Prusiner SB (2012) Cell biology. A unifying role for prions in neurodegenerative diseases. Science 336:1511–1513. https://doi.org/10.1126/science.1222951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Purro SA, Farrow MA, Linehan J, Nazari T, Thomas DX, Chen Z et al (2018) Transmission of amyloid-beta protein pathology from cadaveric pituitary growth hormone. Nature 564:415–419. https://doi.org/10.1038/s41586-018-0790-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Qiang W, Kelley K, Tycko R (2013) Polymorph-specific kinetics and thermodynamics of beta-amyloid fibril growth. J Am Chem Soc 135:6860–6871. https://doi.org/10.1021/ja311963f

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Qiang W, Yau WM, Lu JX, Collinge J, Tycko R (2017) Structural variation in amyloid-beta fibrils from Alzheimer's disease clinical subtypes. Nature 541:217–221. https://doi.org/10.1038/nature20814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Rasmussen J, Mahler J, Beschorner N, Kaeser SA, Hasler LM, Baumann F et al (2017) Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer's disease. Proc Natl Acad Sci USA 114:13018–13023. https://doi.org/10.1073/pnas.1713215114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Reinke AA, Gestwicki JE (2011) Insight into amyloid structure using chemical probes. Chem Biol Drug Des 77:399–411. https://doi.org/10.1111/j.1747-0285.2011.01110.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Ritchie DL, Adlard P, Peden AH, Lowrie S, Le Grice M, Burns K et al (2017) Amyloid-beta accumulation in the CNS in human growth hormone recipients in the UK. Acta Neuropathol 134:221–240. https://doi.org/10.1007/s00401-017-1703-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Robinson JL, Lee EB, Xie SX, Rennert L, Suh E, Bredenberg C et al (2018) Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated. Brain 141:2181–2193. https://doi.org/10.1093/brain/awy146

    Article  PubMed  PubMed Central  Google Scholar 

  155. Rosen RF, Ciliax BJ, Wingo TS, Gearing M, Dooyema J, Lah JJ et al (2010) Deficient high-affinity binding of Pittsburgh compound B in a case of Alzheimer's disease. Acta Neuropathol 119:221–233. https://doi.org/10.1007/s00401-009-0583-3

    Article  CAS  PubMed  Google Scholar 

  156. Rosen RF, Tomidokoro Y, Farberg AS, Dooyema J, Ciliax B, Preuss TM et al (2016) Comparative pathobiology of beta-amyloid and the unique susceptibility of humans to Alzheimer's disease. Neurobiol Aging 44:185–196. https://doi.org/10.1016/j.neurobiolaging.2016.04.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Rosen RF, Walker LC, Levine H 3rd (2011) PIB binding in aged primate brain: enrichment of high-affinity sites in humans with Alzheimer's disease. Neurobiol Aging 32:223–234. https://doi.org/10.1016/j.neurobiolaging.2009.02.011

    Article  CAS  PubMed  Google Scholar 

  158. Ruiz-Riquelme A, Lau HHC, Stuart E, Goczi AN, Wang Z, Schmitt-Ulms G et al (2018) Prion-like propagation of beta-amyloid aggregates in the absence of APP overexpression. Acta Neuropathol Commun 6:26. https://doi.org/10.1186/s40478-018-0529-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Saborio GP, Permanne B, Soto C (2001) Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding. Nature 411:810–813. https://doi.org/10.1038/35081095

    Article  CAS  PubMed  Google Scholar 

  160. Sachse C, Fandrich M, Grigorieff N (2008) Paired beta-sheet structure of an Abeta(1–40) amyloid fibril revealed by electron microscopy. Proc Natl Acad Sci USA 105:7462–7466. https://doi.org/10.1073/pnas.0712290105

    Article  PubMed  PubMed Central  Google Scholar 

  161. Safar JG, Xiao X, Kabir ME, Chen S, Kim C, Haldiman T et al (2015) Structural determinants of phenotypic diversity and replication rate of human prions. PLoS Pathog 11:e1004832. https://doi.org/10.1371/journal.ppat.1004832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Saito T, Suemoto T, Brouwers N, Sleegers K, Funamoto S, Mihira N et al (2011) Potent amyloidogenicity and pathogenicity of Abeta43. Nat Neurosci 14:1023–1032. https://doi.org/10.1038/nn.2858

    Article  CAS  PubMed  Google Scholar 

  163. Salvadores N, Shahnawaz M, Scarpini E, Tagliavini F, Soto C (2014) Detection of misfolded Abeta oligomers for sensitive biochemical diagnosis of Alzheimer's disease. Cell Rep 7:261–268. https://doi.org/10.1016/j.celrep.2014.02.031

    Article  CAS  PubMed  Google Scholar 

  164. Sanders DW, Kaufman SK, DeVos SL, Sharma AM, Mirbaha H, Li A et al (2014) Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82:1271–1288. https://doi.org/10.1016/j.neuron.2014.04.047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Sawaya MR, Sambashivan S, Nelson R, Ivanova MI, Sievers SA, Apostol MI et al (2007) Atomic structures of amyloid cross-beta spines reveal varied steric zippers. Nature 447:453–457. https://doi.org/10.1038/nature05695

    Article  CAS  PubMed  Google Scholar 

  166. Schmidt C, Wolff M, Weitz M, Bartlau T, Korth C, Zerr I (2011) Rapidly progressive Alzheimer disease. Arch Neurol 68:1124–1130. https://doi.org/10.1001/archneurol.2011.189

    Article  PubMed  Google Scholar 

  167. Schmidt M, Rohou A, Lasker K, Yadav JK, Schiene-Fischer C, Fandrich M et al (2015) Peptide dimer structure in an Abeta(1–42) fibril visualized with cryo-EM. Proc Natl Acad Sci USA 112:11858–11863. https://doi.org/10.1073/pnas.1503455112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Schmidt M, Sachse C, Richter W, Xu C, Fandrich M, Grigorieff N (2009) Comparison of Alzheimer Abeta(1–40) and Abeta(1–42) amyloid fibrils reveals similar protofilament structures. Proc Natl Acad Sci USA 106:19813–19818. https://doi.org/10.1073/pnas.0905007106

    Article  PubMed  PubMed Central  Google Scholar 

  169. Sehlin D, Fang XT, Cato L, Antoni G, Lannfelt L, Syvanen S (2016) Antibody-based PET imaging of amyloid beta in mouse models of Alzheimer's disease. Nat Commun 7:10759. https://doi.org/10.1038/ncomms10759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med 8:595–608. https://doi.org/10.15252/emmm.201606210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Shahnawaz M, Mukherjee A, Pritzkow S, Mendez N, Rabadia P, Liu X et al (2020) Discriminating alpha-synuclein strains in Parkinson's disease and multiple system atrophy. Nature 578:273–277. https://doi.org/10.1038/s41586-020-1984-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I et al (2008) Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med 14:837–842. https://doi.org/10.1038/nm1782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Shepherd C, McCann H, Halliday GM (2009) Variations in the neuropathology of familial Alzheimer's disease. Acta Neuropathol 118:37–52. https://doi.org/10.1007/s00401-009-0521-4

    Article  CAS  PubMed  Google Scholar 

  174. Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B et al (2010) The Alzheimer's disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS ONE 5:e9505. https://doi.org/10.1371/journal.pone.0009505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Soto C, Pritzkow S (2018) Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases. Nat Neurosci 21:1332–1340. https://doi.org/10.1038/s41593-018-0235-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Stohr J, Condello C, Watts JC, Bloch L, Oehler A, Nick M et al (2014) Distinct synthetic Abeta prion strains producing different amyloid deposits in bigenic mice. Proc Natl Acad Sci USA 111:10329–10334. https://doi.org/10.1073/pnas.1408968111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Stohr J, Watts JC, Mensinger ZL, Oehler A, Grillo SK, DeArmond SJ et al (2012) Purified and synthetic Alzheimer's amyloid beta (Abeta) prions. Proc Natl Acad Sci USA 109:11025–11030. https://doi.org/10.1073/pnas.1206555109

    Article  PubMed  PubMed Central  Google Scholar 

  178. Tellechea P, Pujol N, Esteve-Belloch P, Echeveste B, Garcia-Eulate MR, Arbizu J et al (2018) Early- and late-onset Alzheimer disease: Are they the same entity? Neurologia 33:244–253. https://doi.org/10.1016/j.nrl.2015.08.002

    Article  CAS  PubMed  Google Scholar 

  179. Telling GC, Parchi P, DeArmond SJ, Cortelli P, Montagna P, Gabizon R et al (1996) Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity. Science 274:2079–2082. https://doi.org/10.1126/science.274.5295.2079

    Article  CAS  PubMed  Google Scholar 

  180. Thal DR, Rub U, Orantes M, Braak H (2002) Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791–1800. https://doi.org/10.1212/wnl.58.12.1791

    Article  PubMed  Google Scholar 

  181. Tran J, Chang D, Hsu F, Wang H, Guo Z (2017) Cross-seeding between Abeta40 and Abeta42 in Alzheimer's disease. FEBS Lett 591:177–185. https://doi.org/10.1002/1873-3468.12526

    Article  CAS  PubMed  Google Scholar 

  182. Tycko R (2015) Amyloid polymorphism: structural basis and neurobiological relevance. Neuron 86:632–645. https://doi.org/10.1016/j.neuron.2015.03.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Vergara C, Houben S, Suain V, Yilmaz Z, De Decker R, Vanden Dries V et al (2019) Amyloid-beta pathology enhances pathological fibrillary tau seeding induced by Alzheimer PHF in vivo. Acta Neuropathol 137:397–412. https://doi.org/10.1007/s00401-018-1953-5

    Article  CAS  PubMed  Google Scholar 

  184. Villain N, Dubois B (2019) Alzheimer's Disease Including Focal Presentations. Semin Neurol 39:213–226. https://doi.org/10.1055/s-0039-1681041

    Article  PubMed  Google Scholar 

  185. Walker L, McAleese KE, Thomas AJ, Johnson M, Martin-Ruiz C, Parker C et al (2015) Neuropathologically mixed Alzheimer's and Lewy body disease: burden of pathological protein aggregates differs between clinical phenotypes. Acta Neuropathol 129:729–748. https://doi.org/10.1007/s00401-015-1406-3

    Article  CAS  PubMed  Google Scholar 

  186. Walti MA, Ravotti F, Arai H, Glabe CG, Wall JS, Bockmann A et al (2016) Atomic-resolution structure of a disease-relevant Abeta(1–42) amyloid fibril. Proc Natl Acad Sci USA 113:E4976–4984. https://doi.org/10.1073/pnas.1600749113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Wang H, Duo L, Hsu F, Xue C, Lee YK, Guo Z (2020) Polymorphic Abeta42 fibrils adopt similar secondary structure but differ in cross-strand side chain stacking interactions within the same beta-sheet. Sci Rep 10:5720. https://doi.org/10.1038/s41598-020-62181-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Wang H, Muiznieks LD, Ghosh P, Williams D, Solarski M, Fang A et al (2017) Somatostatin binds to the human amyloid beta peptide and favors the formation of distinct oligomers. eLife. https://doi.org/10.7554/eLife.28401

    Article  PubMed  PubMed Central  Google Scholar 

  189. Watts JC, Condello C, Stohr J, Oehler A, Lee J, DeArmond SJ et al (2014) Serial propagation of distinct strains of Abeta prions from Alzheimer's disease patients. Proc Natl Acad Sci USA 111:10323–10328. https://doi.org/10.1073/pnas.1408900111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Watts JC, Giles K, Grillo SK, Lemus A, DeArmond SJ, Prusiner SB (2011) Bioluminescence imaging of Abeta deposition in bigenic mouse models of Alzheimer's disease. Proc Natl Acad Sci USA 108:2528–2533. https://doi.org/10.1073/pnas.1019034108

    Article  PubMed  PubMed Central  Google Scholar 

  191. Weissmann C, Li J, Mahal SP, Browning S (2011) Prions on the move. EMBO Rep 12:1109–1117. https://doi.org/10.1038/embor.2011.192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Wickner RB, Edskes HK, Bateman DA, Gorkovskiy A, Dayani Y, Bezsonov EE et al (2015) Yeast prions: proteins templating conformation and an anti-prion system. PLoS Pathog 11:e1004584. https://doi.org/10.1371/journal.ppat.1004584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Wilham JM, Orru CD, Bessen RA, Atarashi R, Sano K, Race B et al (2010) Rapid end-point quantitation of prion seeding activity with sensitivity comparable to bioassays. PLoS Pathog 6:e1001217. https://doi.org/10.1371/journal.ppat.1001217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Wogulis M, Wright S, Cunningham D, Chilcote T, Powell K, Rydel RE (2005) Nucleation-dependent polymerization is an essential component of amyloid-mediated neuronal cell death. J Neurosci 25:1071–1080. https://doi.org/10.1523/JNEUROSCI.2381-04.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Wu JW, Breydo L, Isas JM, Lee J, Kuznetsov YG, Langen R et al (2010) Fibrillar oligomers nucleate the oligomerization of monomeric amyloid beta but do not seed fibril formation. J Biol Chem 285:6071–6079. https://doi.org/10.1074/jbc.M109.069542

    Article  CAS  PubMed  Google Scholar 

  196. Xiao Y, Ma B, McElheny D, Parthasarathy S, Long F, Hoshi M et al (2015) Abeta(1–42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer's disease. Nat Struct Mol Biol 22:499–505. https://doi.org/10.1038/nsmb.2991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Zhang R, Hu X, Khant H, Ludtke SJ, Chiu W, Schmid MF et al (2009) Interprotofilament interactions between Alzheimer's Abeta1-42 peptides in amyloid fibrils revealed by cryoEM. Proc Natl Acad Sci USA 106:4653–4658. https://doi.org/10.1073/pnas.0901085106

    Article  PubMed  PubMed Central  Google Scholar 

  198. Zhang W, Tarutani A, Newell KL, Murzin AG, Matsubara T, Falcon B et al (2020) Novel tau filament fold in corticobasal degeneration. Nature 580:283–287. https://doi.org/10.1038/s41586-020-2043-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Zhao Y, Wu X, Li X, Jiang LL, Gui X, Liu Y et al (2018) TREM2 Is a receptor for beta-amyloid that mediates microglial function. Neuron 97(1023–1031):e1027. https://doi.org/10.1016/j.neuron.2018.01.031

    Article  CAS  Google Scholar 

  200. Ziegler-Waldkirch S, Paolo DE, Sauer JF, Erny D, Savanthrapadian S, Loreth D et al (2018) Seed-induced Abeta deposition is modulated by microglia under environmental enrichment in a mouse model of Alzheimer's disease. EMBO J 37:167–182. https://doi.org/10.15252/embj.201797021

    Article  CAS  PubMed  Google Scholar 

  201. Zou WQ, Puoti G, Xiao X, Yuan J, Qing L, Cali I et al (2010) Variably protease-sensitive prionopathy: a new sporadic disease of the prion protein. Ann Neurol 68:162–172. https://doi.org/10.1002/ana.22094

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank Hannu Kalimo for providing brain images. MI is supported by the Swedish Research Institute and the Wenner-Gren Foundations. JCW acknowledges grant support from the Canadian Institutes of Health Research and Alzheimer Society Canada.

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  1. Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Tower, Rm. 4KD481, 60 Leonard Ave., Toronto, ON, M5T 0S8, Canada

    Heather H. C. Lau, Martin Ingelsson & Joel C. Watts

  2. Department of Biochemistry, University of Toronto, Toronto, Canada

    Heather H. C. Lau, Martin Ingelsson & Joel C. Watts

  3. Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Uppsala, Sweden

    Martin Ingelsson

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Lau, H.H.C., Ingelsson, M. & Watts, J.C. The existence of Aβ strains and their potential for driving phenotypic heterogeneity in Alzheimer’s disease. Acta Neuropathol 142, 17–39 (2021). https://doi.org/10.1007/s00401-020-02201-2

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