The DOI matches its Crossref record; 111 of the 111 references it cites were found in a registry or an index; none of the 24 sources its claims cite is checked for support yet.
Pathogenic protein seeding in alzheimer disease and other neurodegenerative disorders
Open accessAbstract
The misfolding and aggregation of specific proteins is a seminal occurrence in a remarkable variety of neurodegenerative disorders. In Alzheimer disease (the most prevalent cerebral proteopathy), the two principal aggregating proteins are β‐amyloid (Aβ) and tau. The abnormal assemblies formed by conformational variants of these proteins range in size from small oligomers to the characteristic lesions that are visible by optical microscopy, such as senile plaques and neurofibrillary tangles. Pathologic similarities with prion disease suggest that the formation and spread of these proteinaceous lesions might involve a common molecular mechanism—corruptive protein templating. Experimentally, cerebral β‐amyloidosis can be exogenously induced by exposure to dilute brain extracts containing aggregated Aβ seeds. The amyloid‐inducing agent probably is Aβ itself, in a conformation generated most effectively in the living brain. Once initiated, Aβ lesions proliferate within and among brain regions. The induction process is governed by the structural and biochemical nature of the Aβ seed, as well as the attributes of the host, reminiscent of pathogenically variant prion strains. The concept of prionlike induction and spreading of pathogenic proteins recently has been expanded to include aggregates of tau, α‐synuclein, huntingtin, superoxide dismutase‐1, and TDP‐43, which characterize such human neurodegenerative disorders as frontotemporal lobar degeneration, Parkinson/Lewy body disease, Huntington disease, and amyotrophic lateral sclerosis. Our recent finding that the most effective Aβ seeds are small and soluble intensifies the search in bodily fluids for misfolded protein seeds that are upstream in the proteopathic cascade, and thus could serve as predictive diagnostics and the targets of early, mechanism‐based interventions. Establishing the clinical implications of corruptive protein templating will require further mechanistic and epidemiologic investigations. However, the theory that many chronic neurodegenerative diseases can originate and progress via the seeded corruption of misfolded proteins has the potential to unify experimental and translational approaches to these increasingly prevalent disorders. Ann Neurol 2011;70:532–540
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TL;DR
This review argues that many neurodegenerative proteopathies, including Alzheimer’s disease, progress by prion-like corruptive protein templating, in which misfolded protein seeds induce and spread aggregation of Aβ, tau, α-synuclein, and other proteins. It synthesizes experimental seeding evidence and discusses implications for biomarkers, therapeutics, and possible iatrogenic transmission, while noting that clinical implications remain uncertain.
Key findings
- In Alzheimer’s disease, Aβ aggregation is implicated as an early trigger; cerebral Aβ deposition precedes clinical symptoms by a decade or more, and tauopathy correlates strongly with cognitive decline. Oligomeric Aβ, ranging from dimers to dodecamers or larger, may be more deleterious than histologically obvious plaques and cerebral amyloid angiopathy.
- Cerebral β-amyloidosis can be experimentally induced in APP-transgenic mice by intracerebral infusion of brain extracts containing minute amounts of aggregated Aβ. Evidence includes that seeding requires aggregated human-sequence Aβ, is impeded by anti-Aβ immunodepletion, is ineffective in non-transgenic mice, mirrors the donor deposit phenotype, and is abrogated by formic acid denaturation.
- The most potent Aβ seeds appear to be small and soluble, including proteinase K-sensitive species in the 100,000×g soluble fraction; sonication enhances seeding. In contrast, aggregated synthetic Aβ has not significantly induced cerebral Aβ deposition in APP-transgenic mice.
- Tau tangles can be exogenously induced by brain extract containing abnormal tau filaments in Alz17 mice, with time- and region-dependent spread; prion-like propagation has also been implicated for α-synuclein, SOD1, TDP-43, and polyglutamine aggregates. Human prion disease transmission has occurred in fewer than 700 known cases.
Methods
- Narrative review; no new primary data are reported. It synthesizes human neuropathology, genetics, imaging, and transgenic mouse/cell-culture seeding experiments.
- The main analysis is a conceptual synthesis of evidence for corruptive protein templating across Alzheimer’s disease, prion disease, tauopathies, synucleinopathies, amyotrophic lateral sclerosis/frontotemporal lobar degeneration, and Huntington’s disease.
- No systematic search strategy, meta-analysis, or quantitative pooling is described.
Limitations
- Stated: many questions remain, clinical implications are uncertain, and much research on this phenomenon is fragmentary. The paper also states that there is no direct evidence linking non-prion neurodegenerative diseases to seeds arising outside the central nervous system or taken up from the environment.
- Stated: final evidence is lacking that in vivo tau induction occurs via prion-like corruptive templating rather than, for example, activation of a signaling cascade; the mode of cell-to-cell transfer of aggregates is unclear. Transmission of non-prion proteopathies by tainted instruments is a theoretical possibility not demonstrated in humans.
- Evident: as a narrative review, it does not provide systematic search criteria, quantitative synthesis, or primary experimental validation, and some cited findings are described as in press or not fully detailed.
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12 Not checked yet · 8 Own interpretation · 2 No basis given
In the paper
“Our recent finding that the most effective Aβ seeds are small and soluble”
§ Pathogenic Protein Seeding in Alzheimer’s Disease and Other Neurodegenerative Disorders > Abstract
What the sources say
- Not checked yetcites [54] Langer F Eisele YS Fritschi S Staufenbiel M Walker LC Jucker M Soluble Aβ seeds are potent inducers of cerebral β-amyloid deposition J Neuroscience 2011 in press PMC3229270 21994365 source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Using a paradigm similar to in vivo Aβ-seeding, neurofibrillary (tau) tangles can be exogenously induced by the intracerebral infusion of brain extract containing abnormal tau filaments into mice bearing a human tau transgene63.”
§ Pathogenic Protein Seeding in Alzheimer’s Disease and Other Neurodegenerative Disorders > Induction and spread of tau filaments in experimental animals
What the sources say
- Not checked yetcites [63] Clavaguera F Bolmont T Crowther RA Transmission and spreading of tauopathy in transgenic mouse brain Nat Cell Biol 2009 11 909 13 19503072 PMC2726961 source
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In the paper
“The seeded proliferation of misfolded proteins, a concept that arose and evolved in the prion field, holds considerable explanatory power for the pathogenesis of many of the neurodegenerative diseases that afflict our burgeoning elderly population.”
§ Pathogenic Protein Seeding in Alzheimer’s Disease and Other Neurodegenerative Disorders > Conclusion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While the transmission of non-prion proteopathies by tainted instruments thus is a theoretical possibility, proof of such a phenomenon (which could be obscured by a protracted incubation period) has not been demonstrated in humans.”
§ Pathogenic Protein Seeding in Alzheimer’s Disease and Other Neurodegenerative Disorders > Clinical, Practical and Theoretical Implications
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Experimentally, β-amyloid induction can be triggered in transgenic mice by intracerebrally implanted stainless steel wires coated with minute amounts of brain extract rich in aggregated Aβ52 (Fig 2).”
§ Pathogenic Protein Seeding in Alzheimer’s Disease and Other Neurodegenerative Disorders > Clinical, Practical and Theoretical Implications
What the sources say
- Not checked yetcites [52] Eisele YS Bolmont T Heikenwalder M Induction of cerebral beta-amyloidosis: intracerebral versus systemic Abeta inoculation Proc Natl Acad Sci U S A 2009 106 12926 31 19622727 PMC2722323 source
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Once initiated, Aβ lesions proliferate within and among brain regions.”
§ Pathogenic Protein Seeding in Alzheimer’s Disease and Other Neurodegenerative Disorders > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“the (slight) risk of prion transmission by instruments used on patients with undiagnosed prion disease106”
§ Pathogenic Protein Seeding in Alzheimer’s Disease and Other Neurodegenerative Disorders > Clinical, Practical and Theoretical Implications
What the sources say
- Not checked yetcites [106] Ward HJ Everington D Croes EA Sporadic Creutzfeldt-Jakob disease and surgery: a case-control study using community controls Neurology 2002 59 543 8 12196646 source
plainconditional- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Experimentally, cerebral β-amyloidosis can be exogenously induced by exposure to dilute brain extracts containing aggregated Aβ seeds.”
§ Pathogenic Protein Seeding in Alzheimer’s Disease and Other Neurodegenerative Disorders > Abstract
What the sources say
- Not checked yetcites [49] Kane MD Lipinski WJ Callahan MJ Evidence for seeding of beta -amyloid by intracerebral infusion of Alzheimer brain extracts in beta -amyloid precursor protein-transgenic mice J Neurosci 2000 20 3606 11 10804202 PMC6772682 source
- Not checked yetcites [50] Walker LC Callahan MJ Bian F Durham RA Roher AE Lipinski WJ Exogenous induction of cerebral beta-amyloidosis in betaAPP-transgenic mice Peptides 2002 23 1241 7 12128081 source
- Not checked yetcites [51] Meyer-Luehmann M Coomaraswamy J Bolmont T Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host Science 2006 313 1781 4 16990547 source
- Not checked yetcites [52] Eisele YS Bolmont T Heikenwalder M Induction of cerebral beta-amyloidosis: intracerebral versus systemic Abeta inoculation Proc Natl Acad Sci U S A 2009 106 12926 31 19622727 PMC2722323 source
- Not checked yetcites [53] Watts JC Giles K Grillo SK Lemus A DeArmond SJ Prusiner SB Bioluminescence imaging of Abeta deposition in bigenic mouse models of Alzheimer’s disease Proc Natl Acad Sci U S A 2011 108 2528 33 21262831 PMC3038719 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In cell culture, however, the prion-like propagation of α-synuclein lesions has been demonstrated80, 81”
§ Pathogenic Protein Seeding in Alzheimer’s Disease and Other Neurodegenerative Disorders > Induction and spread of protein aggregates linked to other neurodegenerative diseases
What the sources say
- Not checked yetcites [80] Desplats P Lee HJ Bae EJ Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein Proc Natl Acad Sci U S A 2009 106 13010 5 19651612 PMC2722313 source
- Not checked yetcites [81] Hansen C Angot E Bergstrom AL alpha-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells J Clin Invest 2011 121 715 25 21245577 PMC3026723 source
boosteddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The induction and proliferation of proteinaceous aggregates by corruptive protein templating appears to be a common feature of multiple, clinically diverse disorders, although many questions remain to be addressed (Table 1).”
§ Pathogenic Protein Seeding in Alzheimer’s Disease and Other Neurodegenerative Disorders > Clinical, Practical and Theoretical Implications
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Findings from transgenic mouse and cell culture models of protein seeding are representative of the pathogenic process in human neurodegenerative diseases.
- Probably not a substantial claim. 2
- It may state two separate claims as one. 1
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The theoretical framework underlying this paradigm recently has expanded to include an extraordinary array of neurological and systemic disorders.”
§ Pathogenic Protein Seeding in Alzheimer’s Disease and Other Neurodegenerative Disorders > Conclusion
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the clinical implications remain uncertain”
§ Pathogenic Protein Seeding in Alzheimer’s Disease and Other Neurodegenerative Disorders > Conclusion
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“In AD, cerebral β-amyloid deposition begins in humans at least a decade prior to the onset of cognitive decline, and hence is an early and predictive indicator of the disease4.”
§ Pathogenic Protein Seeding in Alzheimer’s Disease and Other Neurodegenerative Disorders > Clinical, Practical and Theoretical Implications
What the sources say
- Not checked yetcites [4] Holtzman DM Morris JC Goate AM Alzheimer’s disease: the challenge of the second century Sci Transl Med 2011 3 77sr1 21471435 PMC3130546
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper relies on this without support.
Findings from transgenic mouse and cell culture models of protein seeding are representative of the pathogenic process in human neurodegenerative diseases.
“Establishing the clinical implications of corruptive protein templating will require further mechanistic and epidemiologic investigations.”
The paper relies on this without support.
Cerebral proteopathies are growing in prevalence.
“the growing prevalence of cerebral proteopathies necessitates a comprehensive quest”
Claims other papers make about this one
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In the citing paper
“A synapse-centred hypothesis also does not preclude the spreading hypothesis [34, 66], which could be either a downstream pathological event or a potential trigger of Tau-related excitotoxicity and synaptic failure.”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [66]
In the citing paper
“The fact that the amyloid tap turns itself off before clinical changes appreciably manifest, we feel, also argues against the idea that Aβ perpetuates itself in a prion-like fashion [261].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [261]
Citations
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RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory
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Understanding the Pathophysiology of Cerebral Amyloid Angiopathy
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Antibodies inhibit transmission and aggregation of C9orf72 poly‐GA dipeptide repeat proteins
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The Prion-Like Properties of Amyloid-β Assemblies: Implications for Alzheimer's DiseasePreprint
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Self-citationPredictive model of spread of Parkinson's pathology using network diffusion
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Metabolic Dysfunction in Alzheimer’s Disease: From Basic Neurobiology to Clinical Approaches
Clarke, J. R., Ribeiro, F. C., Frozza, R. L., Felice, F. G. D., & Lourenco, M. V. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-179911 · Cited by 93
Review: Modulating the unfolded protein response to prevent neurodegeneration and enhance memory
Halliday, M., & Mallucci, G. R. (2014) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12211 · Cited by 85
Recent Progress in Alzheimer’s Disease Research, Part 1: Pathology
Hane, F. T., Lee, B. Y., & Leonenko, Z. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-160882 · Cited by 92
“C) Tau pathology spreads in reverse, beginning in the locus coeruleus and transenterorhinal areas and then spreading to the amygdala and neocortex [122].”
BackgroundBrain structural alterations are distributed following functional, anatomic and genetic connectivity
Cauda, F., Nani, A., Manuello, J., Premi, E., Palermo, S., Tatu, K., Duca, S., Fox, P. T., & Costa, T. (2018) · Brain · doi:10.1093/brain/awy252 · Cited by 77
Fate and propagation of endogenously formed Tau aggregates in neuronal cells
Chastagner, P., Loría, F., Vargas, J., Tois, J., Diamond, M. I., Okafo, G. N., Brou, C., & Zurzolo, C. (2020) · EMBO Molecular Medicine · doi:10.15252/emmm.202012025 · Cited by 80
“…neuronal phospho-Tau first appears in the locus coeruleus and in the trans-entorhinal cortex before it spreads to the hippocampal formation and neocortex, following a predictable pattern (Braak & Braak, 1991; Braak et al, 2011; Jucker & Walker, 2011; Grinberg & Heinsen, 2017; Kaufman et al, 2018).”
BackgroundUwajeh, P. C., Iyendo, T. O., & Polay, M. (2019) · EXPLORE · doi:10.1016/j.explore.2019.05.002 · Cited by 84
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Lehmann, M., Madison, C. M., Ghosh, P. M., Miller, Z., Greicius, M. D., Kramer, J. H., Coppola, G., Miller, B. L., Jagust, W. J., Gorno‐Tempini, M. L., et al. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.06.029 · Cited by 79
“…well understood, converging data from in vitro and in vivo studies in animals and humans support the hypothesis that AD pathology spreads through neural networks (Clavaguera et al., 2009; de Calignon et al., 2012; Jucker and Walker, 2011; Liu et al., 2012; Sepulcre et al., 2013; Zhou et al., 2012).”
Blumenstock, S., Rodrigues, E. F., Peters, F., Blázquez‐Llorca, L., Schmidt, F., Giese, A., & Herms, J. W. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201607305 · Cited by 80
“…on a knife-edge and that perturbations that change its expression produces neurotoxicity with a common mechanism in which the critical events are protein misfolding, aggregate deposition, aggregate propagation, and synaptic dysfunction (Jucker & Walker, 2011; Guo & Lee, 2014; Luna & Luk, 2015).”
BackgroundEisele, Y. S., & Duyckaerts, C. J. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1516-y · Cited by 82
“The spatiotemporal progression of seeded Aβ deposits in APP tg rodents suggests that at least part of the spreading takes place along neuroanatomical pathways [67, 134].”
InfluentialKim, H., Su-Min, K., Park, S.-J., Park, G., Shin, H., Park, M. S., & Kim, J. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.709091 · Cited by 79
Seed-induced acceleration of amyloid-β mediated neurotoxicity in vivo
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“Protein aggregates are a common feature of neurodegenerative diseases, including Alzheimer’s disease (AD) [1].”
BackgroundSong, J., Park, K. H., Lee, W. T., & Lee, J. E. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms15022119 · Cited by 76
“In addition, Aβ leading to AD pathology [11] can activate ASK1 that is required for ROS and ER stress-induced JNK activation [12–15].”
BackgroundScherr, M., Utz, L., Tahmasian, M., Pasquini, L., Grothe, M. J., Rauschecker, J. P., Grimmer, T., Drzezga, A. E., Sorg, C., & Riedl, V. (2019) · Human Brain Mapping · doi:10.1002/hbm.24517 · Cited by 77
“Following a prion-like mechanism, another model suggests downstream spreading to connected cells (Frost & Diamond, 2010; Jucker & Walker, 2011).”
BackgroundPini, L., Jacquemot, C., Cagnin, A., Meneghello, F., Semenza, C., Mantini, D., & Vallesi, A. (2019) · Human Brain Mapping · doi:10.1002/hbm.24790 · Cited by 75
“…in AD and alphasynuclein in PD, can spread in a prion-like fashion via selective functionally connected neural networks, triggering specific clinical phenotypes of brain disorders (Brettschneider, Del Tredici, Lee, & Trojanowski, 2015; Jucker & Walker, 2011; Raj, Kuceyeski, & Weiner, 2012).”
BackgroundCorruption and Spread of Pathogenic Proteins in Neurodegenerative Diseases
Walker, L. C., & LeVine, H. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.r112.399378 · Cited by 75
Self-citationNeuritic and Diffuse Plaque Associations with Memory in Non-Cognitively Impaired Elderly
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“…initiates tau signaling via either an antero-or retrograde transneuronal seeding process similar to the regional propagation of tau in human disease and animal models [58, 59] as A (cid:2) first appears in neocortical regions that have extensivereciprocalconnectionswiththemedialtem-porallobe[60,61].”
Mondragón‐Rodríguez, S., Perry, G. L., Zhu, X., & Boehm, J. (2012) · International Journal of Alzheimer s Disease · doi:10.1155/2012/630182 · Cited by 74
“Overall, the perceived strength of the amyloid cascade hypothesis is reflected in the scientific literature, which is voluminous and dominated by experimental studies that adhere to the following statement: Aβ accumulates in the AD brain, consequently leading to neurodegeneration [19].”
BackgroundInfluentialPrion-like seeding and nucleation of intracellular amyloid-β
Olsson, T. T., Klementieva, O. L., & Gouras, G. K. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.01.015 · Cited by 74
Cremades, N., & Dobson, C. M. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.07.009 · Cited by 72
“…prion protein acts as an infectious agent to propagate prion diseases (Aguzzi, 2009; Soto, 2012; Westermark and Westermark, 2010) and is also likely to be an important factor in the propagation of other amyloidogenic diseases (Brundin et al., 2010; Jucker and Walker, 2011; Walker and Jucker, 2015).”
Oleuropein aglycone and hydroxytyrosol interfere differently with toxic Aβ1-42 aggregation
Leri, M., Natalello, A., Bruzzone, E., Stefani, M., & Bucciantini, M. (2019) · Food and Chemical Toxicology · doi:10.1016/j.fct.2019.04.015 · Cited by 72
Carbon Quantum Dots for Treatment of Amyloid Disorders
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Scialò, C., Cecco, E. D., Manganotti, P., & Legname, G. (2019) · Viruses · doi:10.3390/v11030261 · Cited by 69
“To date, prion diseases are the unique neurodegenerative disorders showing an infectious transmissible protein species capable of recapitulating a clinical disease [3,4] with no clear evidence to the naturally occurring human-to-human transmission of other neurodegenerative conditions [5,6].”
BackgroundArmato, U., Chiarini, A., Chakravarthy, B., Chioffi, F., Pacchiana, R., Colarusso, E., Whitfield, J. F., & Dal Prà, I. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.04.020 · Cited by 68
Tau immunotherapies for Alzheimer’s disease
Hoskin, J. L., Sabbagh, M. N., Al-Hasan, Y. M., & Decourt, B. (2019) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2019.1619694 · Cited by 69
“synaptically transferred from one neuron to the next [31,41,44].”
BackgroundAlzheimer’s Disease: A Clinical Practice-Oriented Review
Alves, L., Correia, A. S., Miguel, R., Alegria, P., & Bugalho, P. (2012) · Frontiers in Neurology · doi:10.3389/fneur.2012.00063 · Cited by 74
“PATHOGENESIS AD is the most frequent cerebral proteopathy (Jucker and Walker, 2011).”
BackgroundPrions: Generation and Spread Versus Neurotoxicity
Halliday, M., Radford, H., & Mallucci, G. R. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.r114.568477 · Cited by 68
Diack, A. B., Ritchie, D. L., Peden, A., et al. (2014) · Emerging infectious diseases · doi:10.3201/eid2012.140214 · Cited by 66
“Prion disease propagation involves the aggregation of abnormal PrP that acts as a template for further aggregation within the brain, a process termed seeding (21,22).”
BackgroundDam, D. V., Vermeiren, Y., Dekker, A. D., Naudé, P. J. W., & Deyn, P. P. D. (2016) · Current Alzheimer Research · doi:10.2174/1567205013666160502123607 · Cited by 68
Interaction between -Synuclein and Other Proteins in Neurodegenerative Disorders
Jellinger, K. A. (2011) · The Scientific World JOURNAL · doi:10.1100/2011/371893 · Cited by 64
Beekes, M., Thomzig, A., Schulz‐Schaeffer, W., & Burger, R. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1324-9 · Cited by 67
“A substantial body of data obtained during the past few years [12, 32, 43, 52] has raised the question as to what extent Aβ-, tau- or α-synuclein aggregates behave like prions—and whether they can possibly transmit disease.”
BackgroundResultInfluentialLaferrière, F., Tixador, P., Moudjou, M., Chapuis, J., Sibille, P., Herzog, L., Reine, F., Jaumain, E., Laude, H., Rézaei, H., et al. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003702 · Cited by 61
“As the most potent inducers of the pathogenesis, these oligomers could be in fine the most neurotoxic, incidentally concurring with the view that the oligomers generated during neurodegenerative diseases linked to protein misfolding and aggregation are generally more potent than larger multimers in impairing neuronal…”
BackgroundReactive Astrocytes as Drug Target in Alzheimer’s Disease
Assefa, B. T., Gebre, A. K., & Altaye, B. M. (2018) · BioMed Research International · doi:10.1155/2018/4160247 · Cited by 66
“Accumulating evidences suggest that, like Aβ, extracellular tau protein also exits the brain via the interstitial bulk flow [98, 112, 113].”
BackgroundIntravenous injection of beta-amyloid seeds promotes cerebral amyloid angiopathy (CAA)
Burwinkel, M., Lutzenberger, M., Heppner, F. L., Schulz‐Schaeffer, W., & Baier, M. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-018-0511-7 · Cited by 61
“The apparent ease of intracerebral transmission suggests that the seeding and spread of A β pathologies in brain tissue may - at least in part - occur in a manner similar to PrP Sc -based prions [2, 13].”
BackgroundCause and consequence of Aβ – Lipid interactions in Alzheimer disease pathogenesis
Rangachari, V., Dean, D. N., Rana, P., Vaidya, A., & Ghosh, P. (2018) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2018.03.004 · Cited by 61
Developments in Tau PET Imaging
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A mechanistic survey of Alzheimer's disease
Tang, Y., Zhang, D., Gong, X., & Zheng, J. (2021) · Biophysical Chemistry · doi:10.1016/j.bpc.2021.106735 · Cited by 66
Developing therapeutic vaccines against Alzheimer’s disease
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“and can seed further pathology in the brain, and therefore could be responsible for the characteristic spread of AD pathology though specific brain regions.[3,4] Furthermore, there is also limited evidence to suggest”
BackgroundKayed, R., Dettmer, U., & Lesné, S. (2020) · Journal of Parkinson s Disease · doi:10.3233/jpd-201965 · Cited by 63
Adhesion molecule L1 binds to amyloid beta and reduces Alzheimer's disease pathology in mice
Djogo, N., Jakovčevski, I., Müller, C., Lee, H. J., Xu, J.-C., Jakovcevski, M., Kügler, S., Loers, G., & Schachner, M. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.04.014 · Cited by 60
“In AD patients brain regions involved in learning, memory and emotions are reduced in size due to neuronal cell death, astrogliosis and synaptic degeneration (Albert, 2011; Hardy, 2006; Jucker and Walker, 2011; Mattson, 2004).”
Mondo, K., Glover, W. B., Murch, S. J., et al. (2014) · Food and Chemical Toxicology · doi:10.1016/j.fct.2014.04.015 · Cited by 59
Progression of Seed‐Induced A β Deposition within the Limbic Connectome
Ye, L., Hamaguchi, T., Fritschi, S. K., Eisele, Y. S., Obermüller, U., Jucker, M., & Walker, L. C. (2015) · Brain Pathology · doi:10.1111/bpa.12252 · Cited by 60
“There is now general agreement that these lesions can be initiated by the prionlike seeding of protein aggregation (31, 36, 37, 54).”
Self-citationBeta-Amyloid and Tau-Protein: Structure, Interaction, and Prion-Like Properties
Tatarnikova, O. G., Орлов, М. А., & Bobkova, N. V. (2015) · Biochemistry (Moscow) · doi:10.1134/s000629791513012x · Cited by 62
“Besides histopathological data [95, 97, 98, 100], during recent years some research teams have demonstrated mechanisms of prion-like propagation of Aβ and Tauprotein [101-105] and described a number of proteins in which an increase in the number of β-folds is the basis for well-known neurodegenerative diseases [90, 92…”
BackgroundAlibhai, J. D., Blanco, R. A., Barria, M. A., Piccardo, P., Caughey, B. W., Perry, V. H., Freeman, T. C., & Manson, J. C. (2016) · PLoS Biology · doi:10.1371/journal.pbio.1002579 · Cited by 58
“Recent studies have suggested that the spread of a number of different misfolded protein species between distinct brain regions occurs in a “prion-like” mechanism and is thought to determine specific brain regions that undergo neurodegeneration (reviewed in [10,11]).”
Alpha-Synuclein Levels in Blood Plasma Decline with Healthy Aging
Koehler, N. K. U., Stransky, E., Meyer, M., Gaertner, S., Shing, M., Schnaidt, M., Celej, M. S., Jovin, T. M., Leyhe, T., Laske, C., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0123444 · Cited by 59
“The three proteins also appear to act in concert by coaggregation [12–16] and propagation through the nervous system tissue in a prion-like manner leading to neuronal death [14,17,18].”
BackgroundPrimary cilia and autophagic dysfunction in Huntington’s disease
Kaliszewski, M., Knott, A. B., & Bossy-Wetzel, E. (2015) · Cell Death & Differentiation · doi:10.1038/cdd.2015.80 · Cited by 55
“of neurodegeneration have reported strong evidence of cell-to-cell transmission of α-synuclein,(126,136) tau and amyloid-β.(141) Moreover, it was recently shown that lentiviral”
BackgroundMoradi, S., Tapak, L., & Afshar, S. (2022) · BioMed Research International · doi:10.1155/2022/5009892 · Cited by 56
“a-Syn forms accumulate in neurons, which can cause Lewy body pathology and dopaminergic neuron dysfunction [4].”
Amyloids and Yeast Prion Biology
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Staphylococcus aureus α-toxin: small pore, large consequences
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“AD is the most common ND and is characterized by irregular β-amyloid (Aβ) and tau accumulation, with large aggregates known as senile plaques and neurofibrillary tangles [78].”
Mello, F. D., Braidy, N., Marçal, H., Guillemin, G. J., Nabavi, S. M., & Neilan, B. A. (2017) · Neurotoxicity Research · doi:10.1007/s12640-017-9780-3 · Cited by 58
“More recently, it has been shown that BMAA is misincorporated into human proteins in place of L-serine (Dunlop et al. 2013), leading to proteinmisfolding as evidenced by abnormal protein aggregation and tangle formation (Jucker and Walker 2011).”
BackgroundGuo, X., Namekata, K., Kimura, A. K., Harada, C., & Harada, T. (2017) · Advances in Biological Regulation · doi:10.1016/j.jbior.2017.08.003 · Cited by 54
Buchanan, H. M., Mackay, M., PALMER, K., Tothová, K., Katsur, M., Platt, B., & Koss, D. J. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-01950-1 · Cited by 58
A scFv antibody targeting common oligomeric epitope has potential for treating several amyloidoses
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Tau modification by the norepinephrine metabolite DOPEGAL stimulates its pathology and propagation
Kang, S. S., Meng, L., Zhang, X., Wu, Z., Mancieri, A., Xie, B., Liu, X., Weinshenker, D., Peng, J., Zhang, Z., et al. (2022) · Nature Structural & Molecular Biology · doi:10.1038/s41594-022-00745-3 · Cited by 55
“The progression of AD pathology follows a remarkably systematic pattern across individuals 43 .”
BackgroundDoes ionizing radiation influence Alzheimer's disease risk?
Begum, N., Wang, B., Mori, M., & Varès, G. (2012) · Journal of Radiation Research · doi:10.1093/jrr/rrs036 · Cited by 56
“Ample evidence suggests that the accumulation of Aβ in the brain of AD patients, resulting from increased production or reduced clearance, is associated with inflammation [14], oxidative stress [15, 16], NFT formation [17], neuronal loss [18] and ultimately results in AD-related cognitive impairment [19].”
BackgroundImaging Alzheimer's disease pathophysiology with PET
Schilling, L. P., Zimmer, E. R., Shin, M., Leuzy, A., Pascoal, T. A., Benedet, A. L., Borelli, W. V., Palmini, A., Gauthier, S. G., & Rosa‐Neto, P. (2016) · Dementia & Neuropsychologia · doi:10.1590/s1980-5764-2016dn1002003 · Cited by 57
Age-Dependent Protein Aggregation Initiates Amyloid-β Aggregation
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“In recent years, understanding the initiation and spread of these hallmark protein aggregates has become a central area of Frontiers in Aging Neuroscience | www.frontiersin.org 1 May 2017 | Volume 9 | Article 138 investigation (Jucker and Walker, 2011).”
BackgroundFreeze, B. S., Acosta, D. M., Pandya, S., Zhao, Y., & Raj, A. (2018) · NeuroImage Clinical · doi:10.1016/j.nicl.2018.01.009 · Cited by 51
“…mechanism, as can other proteins such as tau, beta-amyloid, TDP-43 and Huntingtin, which are implicated in Alzheimer disease, frontotemporal dementia and Huntington disease, respectively (Frost and Diamond, 2010; Angot et al., 2010; Polymenidou and Cleveland, 2012; Jucker and Walker, 2011).”
BackgroundTee, B. L., Longoria-Ibarrola, E. M., & Geschwind, M. D. (2018) · Neurologic Clinics · doi:10.1016/j.ncl.2018.07.005 · Cited by 58
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Alzheimer disease: modeling an Aβ-centered biological network
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Engineering therapeutic protein disaggregases
Shorter, J. (2016) · Molecular Biology of the Cell · doi:10.1091/mbc.e15-10-0693 · Cited by 53
“tubule-binding protein, tau, forms cytoplasmic neurofibrillary tangles in afflicted brain regions (Jucker and Walker, 2011).”
BackgroundVallée, A., Lecarpentier, Y., Guillevin, R., & Vallée, J.-N. (2018) · NeuroMolecular Medicine · doi:10.1007/s12017-018-8486-x · Cited by 54
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Riluzole: a therapeutic strategy in Alzheimer’s disease by targeting the WNT/β-catenin pathway
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“neuroinflammation correlated with neurotoxicity, oxidative stress and cytokine release, are considered as possible underlying causes [10, 11].”
BackgroundBorjabad, A., & Volsky, D. J. (2012) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-012-9409-5 · Cited by 51
“In contrast, AD is primarily an auto “proteopathic” (Jucker and Walker 2011) neurodegenerative disease initiated in neurons by misfolding and aggregation of two specific proteins, amyloid-beta and tau, which in later stages of disease form the characteristic lesions of senile plaques and neurofibrillary tangles (Macci…”
InfluentialHornburg, D., Drepper, C., Butter, F., Meissner, F., Sendtner, M., & Mann, M. (2014) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m113.037291 · Cited by 53
“cascade and the onset of symptoms (63).”
Portelius, E., Lashley, T., Westerlund, A., Persson, R., Fox, N. C., Blennow, K., Révész, T., & Zetterberg, H. (2015) · Neurodegenerative Diseases · doi:10.1159/000369465 · Cited by 51
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Metadata
- Authors
- Jucker, M., & Walker, L. C.
- Affiliations
- Emory University (US)
- Corresponding author
- Jucker, Mathias
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2011-10
- Volume
- 70
- Issue
- 4
- Pages
- 532-540
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC3203752
- OpenAlex
- W2018852249
- Semantic Scholar
- a083431598aa8300a06d560a5e6377c2d187348a
- Cited by
- 622
- References
- 111
- Citations by year
- 2026: 9 · 2025: 22 · 2024: 16 · 2023: 26 · 2022: 30 · 2021: 25 · 2020: 45 · 2019: 47 · 2018: 39 · 2017: 47 · 2016: 46 · 2015: 63 · 2014: 58 · 2013: 85 · 2012: 57
- FWCI
- 7.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DZNE Pub (submittedVersion)
- Funders
- U.S. Public Health Service (NCRR RR-00165)
- National Institute on Aging (P01AG026423, P50AG025688)
- National Center for Research Resources (P51RR000165)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, amyloid-beta, tau protein, prion-like propagation, protein aggregation, neurodegenerative diseases, frontotemporal lobar degeneration, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, alpha-synuclein, TDP-43, superoxide dismutase 1, huntingtin, amyloid seeding, diagnostic biomarkers
- MeSH terms
- Alzheimer Disease, Animals, DNA-Binding Proteins, Humans, Prions, Proteins, Amyloid beta-Peptides, tau Proteins, Neurodegenerative Diseases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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