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
plaindirect- Asserted: passes — The authors put it forward as true.
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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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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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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
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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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]
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“The ‘seeding’ hypothesis refers to the idea that misfolded proteins originate in one population of neurons, and then spread pathology to interconnected brain regions via a prionlike process of corruptive templating [105].”
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“Many mechanisms such as genetic factors, chronic inflammation associated with cytokine release, oxidative stress, and trace element neurotoxicity have been suggested as possible underlying causes (Ehrnhoefer et al. 2011; Jucker and Walker 2011).”
BackgroundYang, L., Kress, B. T., Weber, H. J., Thiyagarajan, M., Wang, B., Deane, R., Benveniste, H., Iliff, J. J., & Nedergaard, M. (2013) · Journal of Translational Medicine · doi:10.1186/1479-5876-11-107 · Cited by 317
“Neurodegenerative disorders such as Alzheimer’s disease (AD) are characterized by progressive loss of neurons, sensory and motor impairments, and severe cognitive decline [1].”
BackgroundDunlop, R. A., Cox, P. A., Banack, S. A., & Rodgers, K. J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0075376 · Cited by 315
“Incorporation of BMAA into proteins in vivo might therefore be capable of generating misfolded proteins that can ‘seed’ further protein aggregation in cells [33].”
BackgroundThe Brainstem Pathologies of Parkinson's Disease and Dementia with Lewy Bodies
Seidel, K., Mahlke, J., Siswanto, S., Krüger, R., Heinsen, H., Auburger, G. W. J., Bouzrou, M., Grinberg, L. T., Wicht, H., Korf, H., et al. (2014) · Brain Pathology · doi:10.1111/bpa.12168 · Cited by 301
“In view of the stereotypical topographic progression throughout the brain and the potential transneuronal spread of neuronal pathologies resulting in characteristic brain distribution patterns, PD and DLB are currently suspected to be among the so-called “prion-like” diseases (2, 9, 13, 20, 26, 31, 36, 59, 63, 66).”
Backgroundα‐Synuclein oligomers and clinical implications for Parkinson disease
Kalia, L. V., Kalia, S. K., McLean, P. J., Lozano, A. M., & Lang, A. E. (2012) · Annals of Neurology · doi:10.1002/ana.23746 · Cited by 310
“implicated in disease propagation within the nervous system for many neurodegenerative diseases.(110) Support for a-synuclein seeding and a prion-like process in PD”
BackgroundImmunotherapeutic Approaches for Alzheimer’s Disease
Wisniewski, T., & Goñi, F. (2015) · Neuron · doi:10.1016/j.neuron.2014.12.064 · Cited by 284
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“However, given recent interest in pathogenic Aβ seeding and the spread of amyloid pathology in the AD brain [300], this is an area that could provide some interesting insights into the involvement of the AD vasculature in the early generation and spread of amyloid pathology.”
BackgroundBetulin and its derivatives as novel compounds with different pharmacological effects
Amiri, S., Dastghaib, S., Ahmadi, M., Mehrbod, P., Khadem, F., Behrouj, H., Aghanoori, M., Machaj, F., Ghamsari, M., Rosik, J., et al. (2019) · Biotechnology Advances · doi:10.1016/j.biotechadv.2019.06.008 · Cited by 281
Where, when, and in what form does sporadic Alzheimerʼs disease begin?
Braak, H., & Tredici, K. D. (2012) · Current Opinion in Neurology · doi:10.1097/wco.0b013e32835a3432 · Cited by 261
Modifiable Risk Factors for Alzheimer’s Disease
Edwards III, G. A., Gamez, N., Escobedo Jr., G., Calderon, O., & Moreno-Gonzalez, I. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00146 · Cited by 253
Effect of nutrition on neurodegenerative diseases. A systematic review
Bianchi, V. E., Herrera, P. F., & Rizzi, L. (2019) · Nutritional Neuroscience · doi:10.1080/1028415x.2019.1681088 · Cited by 268
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Structure and Aggregation Mechanisms in Amyloids
Almeida, Z. L., & Brito, R. M. M. (2020) · Molecules · doi:10.3390/molecules25051195 · Cited by 258
Deleault, N. R., Piro, J. R., Walsh, D. J., Wang, F., Ma, J., Geoghegan, J. C., & Supattapone, S. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1204498109 · Cited by 241
“It will be intriguing to see how cofactor molecules participate in the pathogenesis of human prion diseases, and other diseases in which protein misfolding appears to spread through the central nervous system (23).”
BackgroundSoluble Aβ Seeds Are Potent Inducers of Cerebral β-Amyloid Deposition
Langer, F., Eisele, Y. S., Fritschi, S. K., Staufenbiel, M., Walker, L. C., & Jucker, M. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.3088-11.2011 · Cited by 237
Self-citationMechanisms of Protein Seeding in Neurodegenerative Diseases
Walker, L. C., Diamond, M. I., Duff, K. E., & Hyman, B. T. (2013) · JAMA Neurology · doi:10.1001/jamaneurol.2013.1453 · Cited by 226
“In a paradigm similar to that used to study the transmission of prion disease, the intracerebral injection of dilute brain extracts from patients with AD induces the formation of senile plaques and cerebral amyloid angiopathy in mice expressing mutant human APP transgenes.(2) Present data indicate that the essential i…”
InfluentialSelf-citationVallée, A., Lecarpentier, Y., Guillevin, R., & Vallée, J.-N. (2017) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmx073 · Cited by 226
“Oxidative stress and chronic inflammation are considered as likely underlying causes of AD [4,5].”
BackgroundGlobal quantitative analysis of the human brain proteome in Alzheimer’s and Parkinson’s Disease
Ping, L., Duong, D. M., Yin, L., Gearing, M., Lah, J. J., Levey, A. I., & Seyfried, N. T. (2018) · Scientific Data · doi:10.1038/sdata.2018.36 · Cited by 221
Morales, R., Moreno‐González, I., & Soto, C. A. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003537 · Cited by 225
“It has been described that about 81% of AD patients are also affected by either T2D or impaired fasting glucose [7].”
BackgroundTherapies in Parkinsonʼs disease
Jankovic, J. J., & Poewe, W. H. (2012) · Current Opinion in Neurology · doi:10.1097/wco.0b013e3283542fc2 · Cited by 223
Rüb, U., Seidel, K., Heinsen, H., Vonsattel, J. P., den Dunnen, W. F., & Korf, H. W. (2016) · Brain Pathology · doi:10.1111/bpa.12426 · Cited by 206
“Although the concept that some human neurodegenerative disorders represent prion-like diseases is currently popular and wellreceived, further studies are necessary to demonstrate that the polyglutamine disease HD is indeed a chronically progredient prionlike protein misfolding disease (9, 11, 21, 39, 53, 57, 60, 64).”
BackgroundInfluentialRaj, A., LoCastro, E., Kuceyeski, A. F., Tosun, D., Relkin, N. R., & Weiner, M. W. (2015) · Cell Reports · doi:10.1016/j.celrep.2014.12.034 · Cited by 210
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“4, for 20 min and washed, slides were incubated overnight in primary antibody mouse IgG anti-human Aβ 82E1 1:1000 (IBL) and/or rabbit antiamylin [25-37] 1:1000 (Peninsula Laboratories) in PBS Triton Buffer 0.”
Fibronectin aggregation in multiple sclerosis lesions impairs remyelination
Stoffels, J. M. J., de Jonge, J. C., Stancic, M., Nomden, A., van Strien, M. E., Ma, D., Šišková, Z., Maier, O., ffrench‐Constant, C., Franklin, R. J. M., et al. (2013) · Brain · doi:10.1093/brain/aws313 · Cited by 214
“After dialysis, the protein content was determined and the presence of aggregates confirmed by western blot.”
BackgroundChidambaram, S. B., Essa, M. M., Rathipriya, A. G., Bishir, M., Ray, B., Mahalakshmi, A. M., Tousif, A. H., Sakharkar, M. K., Kashyap, R. S., Friedland, R. P., et al. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107988 · Cited by 204
Traumatic Brain Injury Induces Tau Aggregation and Spreading
Edwards, G., Zhao, J., Dash, P. K., Soto, C., & Moreno-Gonzalez, I. (2020) · Journal of Neurotrauma · doi:10.1089/neu.2018.6348 · Cited by 195
“23,24 30–37 In pathological conditions, ptau can mislocalize from the axon to the soma and dendrites and can be released from the neurons.”
Deleault, N. R., Walsh, D. J., Piro, J. R., Wang, F., Wang, X., Ma, J., Rees, J. R., & Supattapone, S. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1206999109 · Cited by 184
“It is possible that cofactor molecules also may play a critical role in the pathogenesis of other neurodegenerative diseases in which protein misfolding can spread through the brain, such as Alzheimer’s disease, Parkinson disease, and amyotrophic lateral sclerosis (32).”
BackgroundSchludi, M. H., Bavarian Brain Banking Alliance, May, S., Grässer, F. A., Rentzsch, K., Kremmer, E., Küpper, C., Klopstock, T., Arzberger, T., & Edbauer, D. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1450-z · Cited by 195
“Spreading and seeding have been reported for other intracellular aggregating proteins in neurodegenerative diseases, but have not been claimed to be the main source of toxicity [22, 53].”
BackgroundBourdenx, M., Koulakiotis, N. S., Sanoudou, D., Bézard, E., Dehay, B., & Tsarbopoulos, A. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.07.003 · Cited by 202
“recombinant proteins are often poor seeds (Jucker and Walker, 2011); then, tau aggregation process is not yet described enough”
BackgroundInfluentialFerrer, I. (2012) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2012.03.005 · Cited by 174
“…and spreading of b-amyloid plaques and altered tau species may occur, under appropriate conditions, at a cellular level in a similar way as occurs in prion diseases under appropriate conditions (Frost and Diamond, 2010; Aguzzi and O’Connor, 2010; Goedert et al., 2010; Jucker and Walker, 2011).”
BackgroundMechanisms of Pathogenic Tau and Aβ Protein Spreading in Alzheimer’s Disease
d’Errico, P., & Meyer‐Luehmann, M. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00265 · Cited by 191
“…closely related to cognitive decline years before the onset of clinical symptoms; and (ii) the ability of pathogenic misfolded Aβ and tau to serve as templates to convert their innocuous counterparts into toxic forms in a prion-like manner (Clavaguera et al., 2009; Jucker and Walker, 2011, 2013).”
BackgroundPrecortical Phase of Alzheimer's Disease ( AD )‐Related Tau Cytoskeletal Pathology
Stratmann, K., Heinsen, H., Korf, H., Turco, D. D., Ghebremedhin, E., Seidel, K., Bouzrou, M., Grinberg, L. T., Böhl, J., Wharton, S. B., et al. (2015) · Brain Pathology · doi:10.1111/bpa.12289 · Cited by 175
“Although the presumed start of AD in circumscribed subcortical brain regions and the possible targeted transneuronal spread of its underlying disease process along anatomical pathways may be in support of the currently prevailing idea of AD as a chronic prion-like neurodegenerative disease, further studies are require…”
BackgroundResultInfluentialMolecular Hydrogen as an Emerging Therapeutic Medical Gas for Neurodegenerative and Other Diseases
Ohno, K., Ito, M., Ichihara, M., & Ito, M. (2012) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2012/353152 · Cited by 169
“Alzheimer’s disease is the most common neurodegenerative disease and is characterized by abnormal aggregation of β-amyloid (Aβ) and tau, the large aggregates of which are recognizable as senile plaques and neurofibrillary tangles, respectively [21].”
BackgroundDourlen, P., Kilinc, D., Malmanche, N., Chapuis, J., & Lambert, J.-C. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02004-0 · Cited by 168
“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”
BackgroundTau Oligomers: The Toxic Player at Synapses in Alzheimer’s Disease
Guerrero-Muñoz, M. J., Gerson, J., & Castillo-Carranza, D. L. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00464 · Cited by 168
“In the prion field, the acquisition of β-sheet conformation by a prion protein allows it to seed the misfolding and aggregation of other prion molecules, reviewed by Jucker and Walker (2011).”
BackgroundLi, H., Liu, Y., Tian, D., Tian, L., Ju, X., Qi, L., Wang, Y., & Liang, C. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112163 · Cited by 167
Leuner, K., Müller, W. E., & Reichert, A. S. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8307-4 · Cited by 160
“Several patients suffer from mixed forms of PD and AD associated with not only α-synuclein but also Aß plaques [39, 40].”
BackgroundPassive immunotherapies targeting Aβ and tau in Alzheimer's disease
Plotkin, S. S., & Cashman, N. R. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.105010 · Cited by 161
Fasae, K. D., Abolaji, A. O., Faloye, T. R., Odunsi, A., Oyetayo, B. O., Enya, J. I., Rotimi, J. A., Akinyemi, R., Whitworth, A. J., & Aschner, M. (2021) · Journal of Trace Elements in Medicine and Biology · doi:10.1016/j.jtemb.2021.126779 · Cited by 161
Costanzo, M., & Zurzolo, C. (2013) · Biochemical Journal · doi:10.1042/bj20121898 · Cited by 161
Skin nerve misfolded α‐synuclein in pure autonomic failure and P arkinson disease
Donadio, V. A., Incensi, A., Piccinini, C., Cortelli, P., Giannoccaro, M. P., Baruzzi, A., & Liguori, R. (2015) · Annals of Neurology · doi:10.1002/ana.24567 · Cited by 146
“The lack of in vivo data may hinder our understanding of where abnormal deposits started in these disorders because of their seeding properties, with a widespread diffusion of abnormal neuronal deposits in a late disease stage when autopsy was carried out.(4) We recently showed that misfolded (phosphorylated) asynucle…”
BackgroundLiu, C.-C., Wang, N., Chen, Y., Inoue, Y., Shue, F., Ren, Y., Wang, M., Qiao, W., Ikezu, T. C., Li, Z., et al. (2023) · Nature Immunology · doi:10.1038/s41590-023-01640-9 · Cited by 146
“Interestingly, triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial receptor for apoE 22 , linking two critical genetic risk factors for AD in the microglial pathway.”
BackgroundHaass, C., & Selkoe, D. (2022) · PLOS Biology · doi:10.1371/journal.pbio.3001694 · Cited by 145
“Strikingly, in humans, the TREM2-dependent protective response is triggered by deposition of amyloid seeds (small aggregates of Aβ), which drive the further aggregation and deposition of Aβ [23,52,53]; this can happen >20 years before familial AD patients show cognitive decline [54].”
BackgroundAnnunziata, I., Patterson, A., Helton, D., Hu, H., Moshiach, S., Gomero, E., Nixon, R., & d’Azzo, A. (2013) · Nature Communications · doi:10.1038/ncomms3734 · Cited by 146
Yeast Prions: Structure, Biology, and Prion-Handling Systems
Wickner, R. B., Shewmaker, F. P., Bateman, D. A., Edskes, H. K., Gorkovskiy, A., Dayani, Y., & Bezsonov, E. E. (2015) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00041-14 · Cited by 141
Protein Microgels from Amyloid Fibril Networks
Shimanovich, U., Efimov, I., Mason, T. G., Flagmeier, P., Buell, A. K., Gedanken, A., Linse, S. S., Åkerfeldt, K. S., Dobson, C. M., Weitz, D. A., et al. (2014) · ACS Nano · doi:10.1021/nn504869d · Cited by 143
Current and emerging avenues for Alzheimer's disease drug targets
Loera‐Valencia, R., Cedazo-Mínguez, Á., Kenigsberg, P.-A., Page, G., Duarte, A. I., Giusti, P., Zusso, M., Robert, P. H., Frisoni, G. B., Cattaneo, A., et al. (2019) · Journal of Internal Medicine · doi:10.1111/joim.12959 · Cited by 142
Traumatic brain injury: a risk factor for neurodegenerative diseases
Gupta, R. K., & Sen, N. (2015) · Reviews in the Neurosciences · doi:10.1515/revneuro-2015-0017 · Cited by 143
“In addition, these Aβ peptides can spread from the site of injection to other brain regions as these Aβ accumulations can migrate between axonally interconnected areas (Jucker and Walker, 2011).”
BackgroundIn vitro prion-like behaviour of TDP-43 in ALS
Smethurst, P., Newcombe, J., Troakes, C., Simone, R., Chen, Y., Patani, R., & Sidle, K. C. L. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.08.007 · Cited by 148
“Accumulating evidence implicates a role for prion-like features in a number of neurodegenerative disorders including ALS (Frost and Diamond, 2010; Jucker and Walker, 2011; Polymenidou and Cleveland, 2011).”
BackgroundPrion-like spreading of Alzheimer’s disease within the brain’s connectome
Fornari, S., Schäfer, A., Jucker, M., Goriely, A., & Ellen Kuhl, A. (2019) · Journal of The Royal Society Interface · doi:10.1098/rsif.2019.0356 · Cited by 145
Self-citationAtherosclerosis and Alzheimer - diseases with a common cause? Inflammation, oxysterols, vasculature
Lathe, R., Tsitrina, A. A., & Kotelevtsev, Y. V. (2014) · BMC Geriatrics · doi:10.1186/1471-2318-14-36 · Cited by 141
“Further evidence for transmissibility emerges from APP transgenic models in which mice develop AD-like pathology only late in life ([156] for review).”
BackgroundStribl, C., Samara, A., Trümbach, D., Peis, R., Neumann, M., Fuchs, H., Gailus‐Durner, V., de Angelis, M. H., Rathkolb, B., Wolf, E., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.515940 · Cited by 139
Chiasserini, D., Biscetti, L., Eusebi, P., Salvadori, N., Frattini, G., Simoni, S., Roeck, N. D., Tambasco, N., Stoops, E., Vanderstichele, H., et al. (2017) · Alzheimer s Research & Therapy · doi:10.1186/s13195-017-0276-4 · Cited by 139
“Lewy bodies (DLB) share a central pathogenic theme: the accumulation, in extra- or intracellular deposits, of aggregated and misfolded proteins [1].”
Fundamentals of cross-seeding of amyloid proteins: an introduction
Ren, B., Zhang, Y., Zhang, M., Liu, Y., Zhang, D., Gong, X., Feng, Z., Tang, J., Chang, Y., & Zheng, J. (2019) · Journal of Materials Chemistry B · doi:10.1039/c9tb01871a · Cited by 139
α1-Adrenergic Receptors in Neurotransmission, Synaptic Plasticity, and Cognition
Perez, D. M. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.581098 · Cited by 139
Verstraete, E., Veldink, J. H., van den Berg, L. H., & van den Heuvel, M. P. (2013) · Human Brain Mapping · doi:10.1002/hbm.22258 · Cited by 132
“A similar type of spread has been proposed for other neurodegenerative diseases involving protein aggregates, including Alzheimer’s disease [Eisele et al., 2010; Jucker and Walker, 2011].”
Backgroundβ-Amyloid and the Pathomechanisms of Alzheimer’s Disease: A Comprehensive View
Penke, B., Bogár, F., & Fülöp, L. (2017) · Molecules · doi:10.3390/molecules22101692 · Cited by 150
Modeling Lewy pathology propagation in Parkinson's disease
Luk, K. C., & Lee, V. M. ‐. (2013) · Parkinsonism & Related Disorders · doi:10.1016/s1353-8020(13)70022-1 · Cited by 132
“These observations augment a converging hypothesis among major neurodegenerative disorders that transmission of the disease protein plays a critical role in progression [29].”
BackgroundInteraction between pathogenic proteins in neurodegenerative disorders
Jellinger, K. A. (2011) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2011.01507.x · Cited by 132
“The propagation of aSyn lesions by cell-to-cell passage has been demonstrated, as has the induction of proteinaceous lesions associated with other NDDs [262], such as aggregates of superoxide dismutase 1 (SOD1) in ALS [250, 251], aggregates of polyamine [228], which typify HD and spinocerebellar ataxias, or cytosolic…”
BackgroundInfluentialBraak, H., & Tredici, K. D. (2016) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a023630 · Cited by 132
Burke, K. A., Yates, E. A., & Legleiter, J. (2013) · Frontiers in Neurology · doi:10.3389/fneur.2013.00017 · Cited by 127
“The ability to circumvent the lag-phase of amyloid formation by adding preformed aggregates in a process called seeding (Jarrett and Lansbury, 1993; Lansbury, 1997; Paravastu et al., 2006; Nonaka et al., 2010; Jucker and Walker, 2011; Serem et al., 2011), demonstrating that such seeds can impose aberrant structure on…”
BackgroundRapid β-Amyloid Deposition and Cognitive Impairment After Cholinergic Denervation in APP/PS1 Mice
Ramos‐Rodríguez, J. J., Pacheco‐Herrero, M., Thyssen, D. H., Murillo-Carretero, M. I., Berrocoso, E., Spires‐Jones, T. L., Bacskai, B. J., & Garcı́a-Alloza, M. (2013) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e318288a8dd · Cited by 125
Gomes, L. A., Hipp, S. A., Rijal Upadhaya, A., Balakrishnan, K., Ospitalieri, S., Koper, M. J., Largo-Barrientos, P., Uytterhoeven, V., Reichwald, J., Rabe, S., et al. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02053-5 · Cited by 125
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“By and large, Aβ neuropathology first seems to hit brain regions that are important for cognition (including learning and memory), and affect regions that play a role in other brain functions in later stages of the disease (Bero et al., 2011; Jucker and Walker, 2011; Pievani et al., 2011).”
Weickenmeier, J., Jucker, M., Goriely, A., & Ellen Kuhl, A. (2018) · Journal of the Mechanics and Physics of Solids · doi:10.1016/j.jmps.2018.10.013 · Cited by 126
“These stereotypical patterns suggest that axonal transport plays a major role in the spreading of misfolded protein ( Jucker and Walker, 2011 ).”
BackgroundSelf-citationThinking laterally about neurodegenerative proteinopathies
Golde, T. E., Borchelt, D., Giasson, B. I., & Lewis, J. M. (2013) · Journal of Clinical Investigation · doi:10.1172/jci66029 · Cited by 126
“19–21 ).”
BackgroundSmall-molecule PET Tracers for Imaging Proteinopathies
Mathis, C. A., Lopresti, B. J., Ikonomović, M. D., & Klunk, W. E. (2017) · Seminars in Nuclear Medicine · doi:10.1053/j.semnuclmed.2017.06.003 · Cited by 124
Exogenous seeding of cerebral β‐amyloid deposition in βAPP‐transgenic rats
Rosen, R. F., Fritz, J. J., Dooyema, J. M., Cintron, A. F., Hamaguchi, T., Lah, J. J., LeVine, H., Jucker, M., & Walker, L. C. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07551.x · Cited by 126
Self-citationAA amyloidosis: basic knowledge, unmet needs and future treatments
Obici, L. P., & Merlini, G. (2012) · Swiss Medical Weekly · doi:10.4414/smw.2012.13580 · Cited by 120
Norepinephrine metabolite DOPEGAL activates AEP and pathological Tau aggregation in locus coeruleus
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“The progression of AD pathology follows a remarkably systematic pattern across individuals, and aberrant forms of Tau are capable of neuron-to-neuron propagation via a prion-like process of corruptive templating (15).”
BackgroundNaldi, M., Fiori, J., Pistolozzi, M., Drake, A., Bertucci, C., Wu, R., Młynarczyk, K., Filipek, S., Simone, A. D., & Andrisano, V. (2012) · ACS Chemical Neuroscience · doi:10.1021/cn3000982 · Cited by 105
Evidence of amyloid-β cerebral amyloid angiopathy transmission through neurosurgery
Jaunmuktane, Z., Quaegebeur, A., Taipa, R. J. F., Baptista, M. V., Barbosa, R. P., Koriath, C., Sciot, R., Mead, S., & Brandner, S. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1822-2 · Cited by 118
“The experimental seeding of amyloid-β (Aβ), the most common misfolded protein in the ageing brain, has been demonstrated in animal models [1, 17, 26].”
BackgroundJanefjord, E., Mååg, J. L. V., Harvey, B. S., & Smid, S. D. (2014) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-013-9984-x · Cited by 118
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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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