Abstract
Neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, are characterized by the aggregation of misfolded proteins, including Aβ, tau and α-synuclein. It is well recognized that these misfolded proteins are able to self-propagate and spread throughout the nervous system and cause neuronal injury in a way that resembles prion disease. These disease-specific misfolded proteins demonstrate unique features, including the seeding barrier, the conformational memory effect, strain selection and strain evolution, based on the presence of various strains. However, the accurate definition of the term strain remains to be clarified. Here, a clear interpretation is proposed by a retrospective of its history in prion research and the recent progress in neurodegeneration research. Furthermore, the causes contributing to the genesis of various strains are also summarized. Deeper insight into strains helps us to understand the phenomena we observe in this field and it also enlightens us on the elusive mechanisms and management of neurodegeneration.
Similar content being viewed by others
References
Goedert M (2015) Alzheimer’s and Parkinson’s diseases: the prion concept in relation to assembled Aβ, tau, and α-synuclein. Science 349:1255555
Goedert M et al (2014) Prion-like mechanisms in the pathogenesis of tauopathies and synucleinopathies. Curr Neurol Neurosci Rep 14:495
Frost B, Diamond MI (2010) Prion-like mechanisms in neurodegenerative diseases. Nat Rev Neurosci 11:155–159
Stopschinski BE, Diamond MI (2017) The prion model for progression and diversity of neurodegenerative diseases. Lancet Neurol 16:323–332
Clavaguera F et al (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11:909–913
Peelaerts W et al (2015) α-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 522:340–344
Kaufman SK et al (2016) Tau prion strains dictate patterns of cell pathology, progression rate, and regional vulnerability in vivo. Neuron 92:796–812
Luk KC et al (2012) Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338:949–953
Foster JD et al (2001) Clinical signs, histopathology and genetics of experimental transmission of BSE and natural scrapie to sheep and goats. Vet. Rec 148:165–171
Jeffrey M et al (1995) Pathology of the transmissible spongiform encephalopathies with special emphasis on ultrastructure. Micron 26:277–298
Pattison IH (1972) Scrapie—a personal view. J Clin Pathol Suppl (R Coll Pathol) 6:110–114
Pattison IH et al (1959) Experimental production of scrapie in goats. J Comp Pathol 69:300–312
Wemheuer WM et al (2017) Types and strains: their essential role in understanding protein aggregation in neurodegenerative diseases. Front, Aging Neurosci, p 9
Aguzzi A et al (2007) Insights into prion strains and neurotoxicity. Nat Rev Mol Cell Biol 8:552–561
Chandler RL (1962) Encephalopathy in mice. Lancet 279:107–108
Chandler RL, Fisher J (1963) Experimental transmission of scrapie to rats. Lancet Lond Engl 2:1165
Chandler RL (1961) Encephalopathy in mice produced by inoculation with scrapie brain material. Lancet Lond Engl 1:1378–1379
Dickinson AG, Meikle VM (1971) Host-genotype and agent effects in scrapie incubation: change in allelic interaction with different strains of agent. Mol Gen Genet MGG 112:73–79
Dickinson AG et al (1972) Competition between different scrapie agents in mice. Nat N Biol 237:244–245
Fraser H, Dickinson AG (1968) The sequential development of the brain lesion of scrapie in three strains of mice. J Comp Pathol 78:301–311
Bruce ME et al (1991) The disease characteristics of different strains of scrapie in Sinc congenic mouse lines: implications for the nature of the agent and host control of pathogenesis. J Gen Virol 72(Pt 3):595–603
Carp RI, Callahan SM (1991) Variation in the characteristics of 10 mouse-passaged scrapie lines derived from five scrapie-positive sheep. J Gen Virol 72(Pt 2):293–298
Watson JD, Crick FH (1953) Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid. Nature 171:737–738
Crick F (1970) Central dogma of molecular biology. Nature 227:561–563
Gajdusek DC, Gibbs CJ (1968) Slow, latent and temperate virus infections of the central nervous system. Res Publ Assoc Res Nerv Ment Dis 44:254–280
Gajdusek DC (1967) Slow-virus infections of the nervous system. N Engl J Med 276:392–400
Eklund CM et al (1967) Pathogenesis of scrapie virus infection in the mouse. J Infect Dis 117:15–22
Sigurdsson B (1954) A chronic encephalitis of sheep: with general remarks on infections which develop slowly and some of their special characteristics. Br Vet J 110:341–354
Manuelidis L et al (2007) Cells infected with scrapie and Creutzfeldt-Jakob disease agents produce intracellular 25-nm virus-like particles. Proc Natl Acad Sci USA 104:1965–1970
Alper T (1985) Scrapie agent unlike viruses in size and susceptibility to inactivation by ionizing or ultraviolet radiation. Nature 317:750
Field EJ et al (1969) Susceptibility of scrapie agent to ionizing radiation. Nature 222:90–91
Hao W (2011) Evidence of intra-segmental homologous recombination in influenza A virus. Gene 481:57–64
De A et al (2016) Bioinformatics studies of Influenza A hemagglutinin sequence data indicate recombination-like events leading to segment exchanges. BMC Res Notes 9:222
Gibson W et al (2015) Genetic recombination between human and animal parasites creates novel strains of human pathogen. PLoS Negl Trop Dis 9:e0003665
Igel-Egalon A et al (2018) Prion strains and transmission barrier phenomena. Pathog Basel Switz 7:E5
Nizynski B et al (2018) Amyloidogenic cross-seeding of Tau protein: transient emergence of structural variants of fibrils. PLoS One 13:e0201182
Scialò C et al (2019) Prion and prion-like protein strains: deciphering the molecular basis of heterogeneity in neurodegeneration. Viruses 11:261
Collinge J, Clarke AR (2007) A general model of prion strains and their pathogenicity. Science 318:930–936
He Z et al (2017) Amyloid-β plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med 24:29–38
Yu X et al (2012) Cross-seeding and conformational selection between three- and four-repeat human Tau proteins. J Biol Chem 287:14950–14959
Condello C, Stöehr J (2018) Aβ propagation and strains: implications for the phenotypic diversity in Alzheimer’s disease. Neurobiol Dis 109:191–200
Mann DMA (1988) Alzheimer’s disease and Down’s syndrome. Histopathology 13:125–137
Scheltens P et al (2016) Alzheimer’s disease. Lancet Lond Engl 388:505–517
Cole SL, Vassar R (2007) The Alzheimer’s disease β-secretase enzyme, BACE1. Mol Neurodegener 2:22
Yang G et al (2019) Structural basis of Notch recognition by human γ-secretase. Nature 565:192–197
Zhang S et al (2017) Insights into formation and structure of Aβ oligomers cross-linked via tyrosines. J Phys Chem. B 121:5523–5535
Zhang S et al (2019) Elucidating the role of hydroxylated phenylalanine in the formation and structure of cross-linked Aβ oligomers. J Phys Chem B 123:1068–1084
Wang Z-X et al (2016) The essential role of soluble Aβ oligomers in Alzheimer’s disease. Mol Neurobiol 53:1905–1924
Ji L et al (2016) Intracellular Aβ and its pathological role in Alzheimer’s disease: lessons from cellular to animal models. Curr Alzheimer Res 13:621–630
Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8:595–608
Fritschi SK et al (2014) Aβ seeds resist inactivation by formaldehyde. Acta Neuropathol. (Berl.) 128:477–484
Heilbronner G et al (2013) Seeded strain-like transmission of β-amyloid morphotypes in APP transgenic mice. EMBO Rep 14:1017–1022
Petkova AT et al (2005) Self-propagating, molecular-level polymorphism in Alzheimer’s b-amyloid fibrils. Science 307:5
Selivanova OM et al (2018) To be fibrils or to be nanofilms? Oligomers are building blocks for fibril and nanofilm formation of fragments of Aβ peptide. Langmuir ACS J Surf Coll 34:2332–2343
Watts JC et al (2014) Serial propagation of distinct strains of A prions from Alzheimer’s disease patients. Proc Natl Acad Sci 111:10323–10328
Rosen RF et al (2010) Deficient high-affinity binding of Pittsburgh compound B in a case of Alzheimer’s disease. Acta Neuropathol (Berl.) 119:221–233
Gurol ME et al (2016) Florbetapir-PET to diagnose cerebral amyloid angiopathy: a prospective study. Neurology 87:2043–2049
Landau SM et al (2016) Amyloid negativity in patients with clinically diagnosed Alzheimer disease and MCI. Neurology 86:1377–1385
Johnson KA et al (2007) Imaging of amyloid burden and distribution in cerebral amyloid angiopathy. Ann Neurol 62:229–234
Johnson KA et al (2013) Florbetapir (F18-AV-45) PET to assess amyloid burden in Alzheimer’s disease dementia, mild cognitive impairment, and normal aging. Alzheimers Dement 9:S72–S83
De-Paula VJ et al (2012) Alzheimer’s disease. Subcell Biochem 65:329–352
Medina M et al (2016) New features about Tau function and dysfunction. Biomolecules 6:21
Borna H et al (2018) Structure, function and interactions of Tau: particular focus on potential drug targets for the treatment of tauopathies. CNS Neurol Disord Drug Targets 17:325–337
Duka V et al (2013) Identification of the sites of tau hyperphosphorylation and activation of tau kinases in synucleinopathies and Alzheimer’s diseases. PLoS One 8:e75025
Yoshida H, Goedert M (2012) Phosphorylation of microtubule-associated protein tau by AMPK-related kinases. J Neurochem 120:165–176
Martin L et al (2013) Tau protein kinases: involvement in Alzheimer’s disease. Ageing Res Rev 12:289–309
Yu Y et al (2009) Developmental regulation of tau phosphorylation, tau kinases, and tau phosphatases. J Neurochem 108:1480–1494
Cavallini A et al (2013) An unbiased approach to identifying tau kinases that phosphorylate tau at sites associated with Alzheimer disease. J Biol Chem 288:23331–23347
Furukawa Y et al (2011) Tau protein assembles into isoform- and disulfide-dependent polymorphic fibrils with distinct structural properties. J Biol Chem 286:27236–27246
Aoyagi H et al (2007) Fibrillogenic nuclei composed of P301L mutant tau induce elongation of P301L tau but not wild-type tau. J Biol Chem 282:20309–20318
Spillantini MG et al (1998) α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci 95:6469–6473
Spillantini MG et al (1997) α-Synuclein in Lewy bodies. Nature 388:839–840
Tu PH et al (1998) Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble α-synuclein. Ann Neurol 44:415–422
Villar-Piqué A et al (2016) Structure, function and toxicity of alpha-synuclein: the Bermuda triangle in synucleinopathies. J Neurochem 139(Suppl 1):240–255
Klingelhoefer L, Reichmann H (2017) The gut and nonmotor symptoms in Parkinson’s disease. Int Rev Neurobiol 134:787–809
Caputi V, Giron MC (2018) Microbiome-Gut-brain axis and toll-like receptors in Parkinson’s disease. Int J Mol, Sci, p 19
Li Y et al (2018) Amyloid fibril structure of α-synuclein determined by cryo-electron microscopy. Cell Res 28:897–903
Tanaka G et al (2019) Biochemical and morphological classification of disease-associated alpha-synuclein mutants aggregates. Biochem Biophys Res Commun 508:729–734
Tanaka G et al (2019) Sequence- and seed-structure-dependent polymorphic fibrils of alpha-synuclein. Biochim Biophys Acta BBA Mol Basis Dis 1865:1410–1420
Atsmon-Raz Y, Miller Y (2016) Non-amyloid-β component of human α-synuclein oligomers induces formation of new Aβ oligomers: insight into the mechanisms that link Parkinson’s and Alzheimer’s diseases. ACS Chem Neurosci 7:46–55
Castillo-Carranza DL et al (2018) α-Synuclein oligomers induce a unique toxic tau strain. Biol Psychiatry 84:499–508
Oikawa T et al (2016) α-Synuclein fibrils exhibit gain of toxic function, promoting tau aggregation and inhibiting microtubule assembly. J Biol Chem 291:15046–15056
Peng C et al (2018) Cellular milieu imparts distinct pathological α-synuclein strains in α-synucleinopathies. Nature 557:558–563
Yamasaki TR et al (2019) Parkinson’s disease and multiple system atrophy have distinct α-synuclein seed characteristics. J Biol Chem 294:1045–1058
Fang B et al (2010) Hypothesis on the relationship between the change in intracellular pH and incidence of sporadic Alzheimer’s disease or vascular dementia. Int J Neurosci 120:591–595
Yates CM et al (1990) Enzyme activities in relation to pH and lactate in postmortem brain in Alzheimer-type and other dementias. J Neurochem 55:1624–1630
Zhang Z et al (2016) Asparagine endopeptidase is an innovative therapeutic target for neurodegenerative diseases. Expert Opin Ther Targets 20:1237–1245
Lee M-H et al (2018) Somatic APP gene recombination in Alzheimer’s disease and normal neurons. Nature 563:639–645
Rohrback S et al (2018) Genomic mosaicism in the developing and adult brain. Dev Neurobiol 78:1026–1048
Cacciottolo M et al (2017) Particulate air pollutants, APOE alleles and their contributions to cognitive impairment in older women and to amyloidogenesis in experimental models. Transl Psychiatry 7:e1022
Kim SH et al (2012) Rapid doubling of Alzheimer’s amyloid-β40 and 42 levels in brains of mice exposed to a nickel nanoparticle model of air pollution. F1000Research 1:70
Sampson TR et al (2016) Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 167:1469–1480.e12
Li H et al (2018) Amyloid, tau, pathogen infection and antimicrobial protection in Alzheimer’s disease -conformist, nonconformist, and realistic prospects for AD pathogenesis. Transl Neurodegener 7:34
Dominy SS et al (2019) Porphyromonas gingivalis in Alzheimer’s disease brains: evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv 5:eaau3333
Wu Y et al (2019) Microglia and amyloid precursor protein coordinate control of transient Candida cerebritis with memory deficits. Nat Commun 10:58
Kagan BL et al (2012) Antimicrobial properties of amyloid peptides. Mol Pharm 9:708–717
Kumar DKV et al (2016) Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci Transl Med 8:340ra7
Soscia SJ et al (2010) The Alzheimer’s disease-associated amyloid β-protein is an antimicrobial peptide. PLoS One 5:e9505
Bourgade K et al (2015) β-Amyloid peptides display protective activity against the human Alzheimer’s disease-associated herpes simplex virus-1. Biogerontology 16:85–98
Eimer WA et al (2018) Alzheimer’s disease-associated β-amyloid is rapidly seeded by herpesviridae to protect against brain infection. Neuron 99:56–63.e3
Tzeng N-S et al (2018) Anti-herpetic medications and reduced risk of dementia in patients with herpes simplex virus infections—a nationwide, population-based cohort study in Taiwan. Neurotherapeutics 15:417–429
Severance EG et al (2016) Candida albicans exposures, sex specificity and cognitive deficits in schizophrenia and bipolar disorder. Npj Schizophr 2:16018
Qiang L et al (2018) Tau does not stabilize axonal microtubules but rather enables them to have long labile domains. Curr Biol 28:2181–2189.e4
Kotagal V et al (2018) Serotonin, β-amyloid, and cognition in Parkinson disease: serotonin Medications in PD. Ann Neurol 83:994–1002
Hepp DH et al (2016) Distribution and load of amyloid-β pathology in Parkinson disease and dementia with Lewy bodies. J Neuropathol Exp Neurol 75:936–945
Nemani SK et al (2018) Co-occurrence of chronic traumatic encephalopathy and prion disease. Acta Neuropathol Commun 6:140
Edwards G et al (2017) Amyloid-beta and tau pathology following repetitive mild traumatic brain injury. Biochem Biophys Res Commun 483:1137–1142
Rubenstein R et al (2017) Tau phosphorylation induced by severe closed head traumatic brain injury is linked to the cellular prion protein. Acta Neuropathol Commun 5:30
Stein TD et al (2015) Beta-amyloid deposition in chronic traumatic encephalopathy. Acta Neuropathol (Berl) 130:21–34
Mufson EJ et al (2016) Progression of tau pathology within cholinergic nucleus basalis neurons in chronic traumatic encephalopathy: a chronic effects of neurotrauma consortium study. Brain Inj 30:1399–1413
Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (No. 81822016, 81771382, and 81571249) to Z. Zhang.
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Tian, Y., Meng, L. & Zhang, Z. What is strain in neurodegenerative diseases?. Cell. Mol. Life Sci. 77, 665–676 (2020). https://doi.org/10.1007/s00018-019-03298-9
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00018-019-03298-9