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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Written from the paper’s full text.
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.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
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Claims the paper makes
0 of 24 cited sources checked · 0 supported · 0 flagged
- Findingown data
The most effective Aβ seeds are small and soluble.
“Our recent finding that the most effective Aβ seeds are small and soluble”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [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
Not checked in the free run.
- Premisecitation
Neurofibrillary (tau) tangles can be exogenously induced by the intracerebral infusion of brain extract containing abnormal tau filaments into mice bearing a human tau transgene.
“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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [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
Not checked in the free run.
- Interpretationnone given
The seeded proliferation of misfolded proteins has considerable explanatory power for the pathogenesis of many neurodegenerative diseases affecting the elderly.
“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.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Transmission of non-prion proteopathies by tainted instruments has not been demonstrated in humans.
“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.”
Quote in the paperSubstantial claim - Premisecitation
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 Aβ.
“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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [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 in the free run.
- Premisereasoning
Once initiated, Aβ lesions proliferate within and among brain regions.
“Once initiated, Aβ lesions proliferate within and among brain regions.”
Quote in the paperSubstantial claim - Premisecitation
There is a slight risk of prion transmission by instruments used on patients with undiagnosed prion disease.
“the (slight) risk of prion transmission by instruments used on patients with undiagnosed prion disease106”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [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
Not checked in the free run.
- Premisecitation
Cerebral β-amyloidosis can be exogenously induced by exposure to dilute brain extracts containing aggregated Aβ seeds.
“Experimentally, cerebral β-amyloidosis can be exogenously induced by exposure to dilute brain extracts containing aggregated Aβ seeds.”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [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 in the free run.
- cites [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 in the free run.
- cites [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 in the free run.
- cites [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 in the free run.
- cites [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
Not checked in the free run.
- Premisecitation
In cell culture, the prion-like propagation of α-synuclein lesions has been demonstrated.
“In cell culture, however, the prion-like propagation of α-synuclein lesions has been demonstrated80, 81”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [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 in the free run.
- cites [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
Not checked in the free run.
- Interpretationreasoning
The induction and proliferation of proteinaceous aggregates by corruptive protein templating appears to be a common feature of multiple, clinically diverse disorders.
“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).”
Quote in the paperSubstantial claim- 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.
- Premisecitation
Prion disease has been transmitted to humans by contaminated neurosurgical instruments in rare instances.
“In rare instances, prion disease has been transmitted to humans by contaminated neurosurgical instruments34.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [34] Belay ED Schonberger LB The public health impact of prion diseases Annu Rev Public Health 2005 26 191 212 15760286 source
Not checked in the free run.
- Interpretationreasoning
Soluble Aβ seeds could serve as informative biomarkers in bodily fluids.
“Because the most potent Aβ seeds, like prions97, appear to be relatively small54, soluble Aβ seeds could serve as informative biomarkers in bodily fluids.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [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
Not checked in the free run.
- cites [97] Silveira JR Raymond GJ Hughson AG The most infectious prion protein particles Nature 2005 437 257 61 16148934 PMC1513539 source
Not checked in the free run.
- Interpretationreasoning
Pathologic similarities with prion disease suggest that the formation and spread of proteinaceous lesions might involve a common molecular mechanism, corruptive protein templating.
“Pathologic similarities with prion disease suggest that the formation and spread of these proteinaceous lesions might involve a common molecular mechanism – corruptive protein templating.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [1] Brown P Salazar AM Gibbs CJ Jr. Gajdusek DC Alzheimer’s disease and transmissible virus dementia (Creutzfeldt-Jakob disease) Ann N Y Acad Sci 1982 396 131 43 6758661 source
Not checked in the free run.
- cites [2] Prusiner SB Some speculations about prions, amyloid, and Alzheimer’s disease N Engl J Med 1984 310 661 3 6363926 source
Not checked in the free run.
- cites [3] Gajdusek DC Spontaneous generation of infectious nucleating amyloids in the transmissible and nontransmissible cerebral amyloidoses Mol Neurobiol 1994 8 1 13 8086124 source
Not checked in the free run.
- Interpretationreasoning
The amyloid-inducing agent probably is Aβ itself, in a conformation generated most effectively in the living brain.
“The amyloid-inducing agent probably is Aβ itself, in a conformation generated most effectively in the living brain.”
Quote in the paperNot a substantial claim - Premisecitation
Templated modification of protein structure subserves the transfer and storage of useful biological information in systems ranging from microbes to mammals.
“Moreover, the templated modification of protein structure also subserves the transfer and storage of useful biological information in systems ranging from microbes to mammals107-110.”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [107] Shorter J Lindquist S Prions as adaptive conduits of memory and inheritance Nat Rev Genet 2005 6 435 50 15931169 source
Not checked in the free run.
- cites [108] Wickner RB Edskes HK Shewmaker F Nakayashiki T Prions of fungi: inherited structures and biological roles Nat Rev Microbiol 2007 5 611 8 17632572 PMC2376760 source
Not checked in the free run.
- cites [109] Tuite MF Serio TR The prion hypothesis: from biological anomaly to basic regulatory mechanism Nat Rev Mol Cell Biol 2010 11 823 33 21081963 PMC3003427 source
Not checked in the free run.
- cites [110] Norrby E Prions and protein-folding diseases J Intern Med 2011 270 1 14 21481020 source
Not checked in the free run.
- Interpretationreasoning
An effective disease-modifying therapy must be initiated prophylactically, before the disease has inflicted irreversible damage on the brain.
“It is likely, therefore, that an effective disease-modifying therapy must be initiated prophylactically, before the disease has inflicted irreversible damage on the brain.”
Quote in the paperNot a substantial claim- 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.
- Premisenone given
The misfolding and aggregation of specific proteins underlies many chronic neurodegenerative diseases that afflict aging humans.
“the misfolding and aggregation of specific proteins underlies many of the chronic neurodegenerative diseases that afflict aging humans”
Quote in the paperNot a substantial claim - Premisecitation
Direct introduction of the seeding agent into the brain is the most efficient way to induce prion disease and Aβ deposition.
“The most efficient induction of prion disease and Aβ deposition is achieved by direct introduction of the seeding agent into the brain30, 56.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [30] Prusiner SB Prion Biology and Diseases 2004 Cold Spring Harbor Laboratory 2nd ed
Not checked in the free run.
- cites [56] Eisele YS Obermüller U Heilbronner G Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis Science 2010 330 980 2 20966215 PMC3233904 source
Not checked in the free run.
- Interpretationreasoning
Non-prion proteopathies are unlikely to be communicable under everyday circumstances.
“Given our current state of knowledge, we feel that it is unlikely that non-prion proteopathies are communicable under everyday circumstances.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 2
- May combine two claims. 1
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone givenThe theoretical framework of seeded protein misfolding has recently expanded to include an extraordinary array of neurological and systemic disorders.
“The theoretical framework underlying this paradigm recently has expanded to include an extraordinary array of neurological and systemic disorders.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
InterpretationreasoningThe clinical implications of corruptive protein templating remain uncertain.
“the clinical implications remain uncertain”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationIn 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 disease.
“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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] Holtzman DM Morris JC Goate AM Alzheimer’s disease: the challenge of the second century Sci Transl Med 2011 3 77sr1 21471435 PMC3130546
Not checked in the free run.
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?
A synapse-centred hypothesis does not preclude the spreading hypothesis, which could be either a downstream pathological event or a potential trigger of Tau-related excitotoxicity and synaptic failure.
“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]
The fact that the amyloid tap turns itself off before clinical changes appreciably manifest argues against the idea that Aβ perpetuates itself in a prion-like fashion.
“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 most infectious prion protein particles
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“Because the most potent A β seeds, like prions 97 , appear to be relatively small 54 , soluble A β seeds could serve as informative biomarkers in bodily fluids.”
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“…aggregates impair neuronal function remains uncertain, but evidence is growing that oligomeric forms of the protein, which can range in size from dimers to dodecamers or larger 14-18 , are more deleterious to brain function than are histologically obvious A β lesions such as senile plaques and CAA.”
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BackgroundIntravesicular Localization and Exocytosis of α-Synuclein and its Aggregates
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BackgroundPrion-like mechanisms in neurodegenerative diseases
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BackgroundNeurodegenerative Diseases and Prions
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BackgroundNeuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease
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Seeding of Normal Tau by Pathological Tau Conformers Drives Pathogenesis of Alzheimer-like Tangles
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Self-citationAmyloids: Not Only Pathological Agents but Also Ordered Nanomaterials
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Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells
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BackgroundThe propagation of prion-like protein inclusions in neurodegenerative diseases
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BackgroundThe Transcellular Spread of Cytosolic Amyloids, Prions, and Prionoids
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BackgroundAmyloid seeds formed by cellular uptake, concentration, and aggregation of the amyloid-beta peptide
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BackgroundCytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates
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Self-citationAnti-Aβ Therapeutics in Alzheimer's Disease: The Need for a Paradigm Shift
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BackgroundInsights into prion strains and neurotoxicity
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“While this phenomenon may result from the direct cross-seeding of tau by aggregated A β 71, 72 , indirect pathways such as A β -induced tau phosphorylation, inflammation, and/or disruption of proteostasis 20, 73-75 have not been ruled out.”
BackgroundCell-to-cell transmission of non-prion protein aggregates
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Self-citationAmyloids, prions and the inherent infectious nature of misfolded protein aggregates
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Soluble Aβ Seeds Are Potent Inducers of Cerebral β-Amyloid Deposition
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The Development of Amyloid β Protein Deposits in the Aged Brain
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“Several lines of evidence49-52 collectively argue that aggregated Aβ in the brain extract is critical for in vivo seeding: (1) The extract is able to seed only if it contains aggregated, human-sequence Aβ; (2) Immunoneutralization/depletion of Aβ in the extract by anti-Aβ antibodies impedes seeding; (3) Seeding of Aβ…”
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BackgroundTransfer of host-derived alpha synuclein to grafted dopaminergic neurons in rat
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BackgroundTHE PUBLIC HEALTH IMPACT OF PRION DISEASES
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Self-citationSporadic Creutzfeldt–Jakob disease and surgery: A case–control study using community controls
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“This cross-seeding is generally less potent than is homologous seeding, but the potential corruption of proteins by exogenous nanoscale materials, some of which may feature amyloidlike structural properties,(103,104) should be factored into safety evaluations of such materials.(41) Furthermore, the cell-to-cell transf…”
BackgroundSelf-citationPrion-like aggregates: infectious agents in human disease
Westermark, G. T., & Westermark, P. (2010) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2010.08.004 · Cited by 82 · see citing works
Deficient high-affinity binding of Pittsburgh compound B in a case of Alzheimer’s disease
Rosen, R. F., Ciliax, B. J., Wingo, T. S., Gearing, M., Dooyema, J. M., Lah, J. J., Ghiso, J. A., LeVine, H., & Walker, L. C. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0583-3 · Cited by 82 · see citing works
Self-citationAn ‘anatomical cascade hypothesis’ for Alzheimer's disease
Hardy, J. (1992) · Trends in Neurosciences · doi:10.1016/0166-2236(92)90033-5 · Cited by 79 · cited 1× · see citing works
“The pattern that emerges from these studies implicates neuronal transport and synaptic exchange mechanisms in the spread of AD lesions within the brain 24-26 .”
BackgroundPrions and protein-folding diseases: Review: Prions and protein-folding diseases
Norrby, E. (2011) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2011.02387.x · Cited by 75 · see citing works
Review: Contribution of transgenic models to understanding human prion disease
Wadsworth, J. D. F., Asante, E. A., & Collinge, J. (2010) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2010.01129.x · Cited by 65 · cited 1× · see citing works
“Experimentally, prion disease has been transmitted to a broad range of species and models.(29,32,33) Fortunately, the transmission of prion disease to humans is unusual, having occurred in <700 known cases, most under extraordinary circumstances such as treatment with human growth hormone derived from cadaveric pituit…”
BackgroundGajdusek, D. C. (1994) · Molecular Neurobiology · doi:10.1007/bf02778003 · Cited by 60 · cited 2× · see citing works
“Several lines of evidence49-52 collectively argue that aggregated Aβ in the brain extract is critical for in vivo seeding: (1) The extract is able to seed only if it contains aggregated, human-sequence Aβ; (2) Immunoneutralization/depletion of Aβ in the extract by anti-Aβ antibodies impedes seeding; (3) Seeding of Aβ…”
BackgroundMolecular polymorphism of Aβ in Alzheimer's disease
LeVine, H., & Walker, L. C. (2008) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2008.05.026 · Cited by 52 · cited 1× · see citing works
“The differential seeding ability of synthetic vs. natural A β aggregates (which may contain additional factors) suggests the possibility that A β , like prions, can misfold into polymorphic and polyfunctional strains 51, 59-62 .”
Self-citationAlzheimer: 100 Years and Beyond
Jucker, M., Beyreuther, K. T., Haass, C., Nitsch, R. M., & Christen, Y. (2006) · Springer eBooks · doi:10.1007/978-3-540-37652-1 · Cited by 50 · cited 1× · see citing works
“…ago, but fundamental insights into the pathogenesis of the disorder emerged only with the identification of the principal proteins that comprise these lesions: A β in senile plaques and cerebral amyloid angiopathy (CAA), and tau in neurofibrillary tangles 4 (for historical references see 5 ).”
BackgroundSelf-citationAlzheimer's Disease and Transmissible Virus Dementia (Creutzfeldt‐Jakob Disease)
BROWN, P., SALAZAR, A. M., GIBBS, C. J., & GAJDUSEK, D. C. (1982) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1982.tb26849.x · Cited by 43 · cited 2× · see citing works
“Several lines of evidence49-52 collectively argue that aggregated Aβ in the brain extract is critical for in vivo seeding: (1) The extract is able to seed only if it contains aggregated, human-sequence Aβ; (2) Immunoneutralization/depletion of Aβ in the extract by anti-Aβ antibodies impedes seeding; (3) Seeding of Aβ…”
BackgroundWalker, L. C., & Jucker, M. (2011) · Nature Neuroscience · doi:10.1038/nn.2853 · Cited by 30 · cited 1× · see citing works
“…and a highly stereotypical appearance of neurofibrillary tangles (Fig 1). β -amyloid plaques develop first in the neocortex, followed by the allocortex and then the subcortex, and the progression of their appearance often corresponds to functionally and anatomically coupled brain regions 21-23 .”
BackgroundSelf-citationPathophysiologie des sporadischen Morbus Parkinson*
Braak, H., & Tredici, K. D. (2010) · Fortschritte der Neurologie · Psychiatrie · doi:10.1055/s-0029-1245179 · Cited by 19 · see citing works
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The amyloid state and its association with protein misfolding diseases.
Knowles, T. P. J., Vendruscolo, M., & Dobson, C. M. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3810 · Cited by 2,382 · see citing works
The glymphatic system: a beginner's guide
Jessen, N. A., Munk, A. S. F., Lundgaard, I., & Nedergaard, M. (2015) · Neurochemical Research · doi:10.1007/s11064-015-1581-6 · Cited by 2,075 · see citing works
“initiation of fibrillary aggregates, which attracts additional tau leading to formation of neurofibrillary tangles ultimately resulting in a prion-like spread of the pathology [101, 102].”
Alzheimer Mechanisms and Therapeutic Strategies
Huang, Y., & Mucke, L. (2012) · Cell · doi:10.1016/j.cell.2012.02.040 · Cited by 1,758 · see citing works
The Amyloid State of Proteins in Human Diseases
Eisenberg, D. S., & Jucker, M. (2012) · Cell · doi:10.1016/j.cell.2012.02.022 · Cited by 1,732 · see citing works
Self-citationSelf-propagation of pathogenic protein aggregates in neurodegenerative diseases
Jucker, M., & Walker, L. C. (2013) · Nature · doi:10.1038/nature12481 · Cited by 1,663 · see citing works
Self-citationThe Intersection of Amyloid Beta and Tau at Synapses in Alzheimer’s Disease
Spires-Jones, T. L., & Hyman, B. T. (2014) · Neuron · doi:10.1016/j.neuron.2014.05.004 · Cited by 1,201 · see citing works
Impairment of Glymphatic Pathway Function Promotes Tau Pathology after Traumatic Brain Injury
Iliff, J. J., Chen, M. J., Plog, B. A., Zeppenfeld, D. M., Soltero, M., Yang, L., Singh, I., Deane, R., & Nedergaard, M. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.3020-14.2014 · Cited by 1,159 · see citing works
“Emerging evidence suggests that the movement of tau and tau aggregates through the extracellular space plays an important role in the development and spread of intracellular tau pathology (Frost and Diamond, 2010; Jucker and Walker, 2011; Walker et al., 2013).”
BackgroundHuntington disease: natural history, biomarkers and prospects for therapeutics
Ross, C. A., Aylward, E. H., Wild, E. J., Langbehn, D. R., Long, J. D., Warner, J. H., Scahill, R. I., Leavitt, B. R., Stout, J. C., Paulsen, J. S., et al. (2014) · Nature Reviews Neurology · doi:10.1038/nrneurol.2014.24 · Cited by 1,016 · see citing works
The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives
Swerdlow, R. H., Burns, J. M., & Khan, S. M. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.09.010 · Cited by 786 · see citing works
Predicting Regional Neurodegeneration from the Healthy Brain Functional Connectome
Zhou, J., Gennatas, E. D., Kramer, J. H., Miller, B. L., & Seeley, W. W. (2012) · Neuron · doi:10.1016/j.neuron.2012.03.004 · Cited by 706 · see citing works
“Providing a more parsimonious account, growing evidence suggests that prion-like mechanisms may promote the spread of toxic, misfolded, nonprion protein species between interconnected neurons (Baker et al., 1993, 1994; Brundin et al., 2010; Clavaguera et al., 2009; Frost and Diamond, 2010; Frost et al., 2009; Hansen e…”
BackgroundInfluentialDistinct α-Synuclein Strains Differentially Promote Tau Inclusions in Neurons
Guo, J. L., Covell, D. J., Daniels, J. P., Iba, M., Stieber, A., Zhang, B., Riddle, D. M., Kwong, L. K., Xu, Y., Trojanowski, J. Q., et al. (2013) · Cell · doi:10.1016/j.cell.2013.05.057 · Cited by 680 · see citing works
Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases
Guo, J. L., & Lee, V. M. Y. (2014) · Nature Medicine · doi:10.1038/nm.3457 · Cited by 641 · see citing works
Cell Biology and Pathophysiology of α-SynucleinPreprint
Burré, J., Sharma, M., & Südhof, T. C. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a024091 · Cited by 575 · see citing works
Bioactive Benzofuran derivatives: A review
Khanam, H., & Shamsuzzaman (2014) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2014.11.039 · Cited by 558 · see citing works
“A major hallmark of AD is the formation and accumulation of fibrillar β-amyloid (Aβ) peptides in the brain [119,120].”
BackgroundThe preclinical phase of the pathological process underlying sporadic Alzheimer’s disease
Braak, H., & Del Tredici, K. (2015) · Brain · doi:10.1093/brain/awv236 · Cited by 540 · see citing works
“…tau protein in the recipient neuron (Brundin et al., 2010; Frost and Diamond, 2010; Goedert et al., 2010, 2014; Braak and Del Tredici, 2011b, 2015b; Jucker and Walker, 2011; Lee et al., 2011; Prusiner, 2012; Clavaguera et al., 2013b, 2014; Duyckaerts, 2013; Pooler et al., 2013; but see also Beekes…”
BackgroundMeal frequency and timing in health and disease
Mattson, M. P., Allison, D. B., Fontana, L., Harvie, M., Longo, V. D., Malaisse, W. J., Mosley, M., Notterpek, L. M., Ravussin, É., Scheer, F. A. J. L., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1413965111 · Cited by 533 · see citing works
ApoE4 Accelerates Early Seeding of Amyloid Pathology
Liu, C.-C., Zhao, N., Fu, Y., Wang, N., Linares, C., Tsai, C.-W., & Bu, G. (2017) · Neuron · doi:10.1016/j.neuron.2017.11.013 · Cited by 451 · see citing works
Physicochemical Properties of Cells and Their Effects on Intrinsically Disordered Proteins (IDPs)
Theillet, F., Binolfi, A., Frembgen-Kesner, T., Hingorani, K. S., Sarkar, M., Kyne, C., Li, C., Crowley, P. B., Gierasch, L. M., Pielak, G. J., et al. (2014) · Chemical Reviews · doi:10.1021/cr400695p · Cited by 504 · see citing works
The activities of amyloids from a structural perspective
Riek, R., & Eisenberg, D. S. (2016) · Nature · doi:10.1038/nature20416 · Cited by 504 · see citing works
The expanding amyloid family: Structure, stability, function, and pathogenesis
Sawaya, M. R., Hughes, M. P., Rodriguez, J. A., Riek, R., & Eisenberg, D. S. (2021) · Cell · doi:10.1016/j.cell.2021.08.013 · Cited by 475 · see citing works
Stancu, I.-C., Cremers, N., Vanrusselt, H., Couturier, J., Vanoosthuyse, A., Kessels, S., Lodder, C., Brône, B., Huaux, F., Octave, J.-N., et al. (2019) · Acta Neuropathologica · doi:10.1007/s00401-018-01957-y · Cited by 447 · see citing works
Neurodegenerative Diseases: Expanding the Prion Concept
Walker, L. C., & Jucker, M. (2015) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-071714-033828 · Cited by 361 · see citing works
“Critical insights into this phenomenon will emerge from a deeper comprehension of the molecular mechanisms that regulate inductive protein folding (Jucker & Walker 2011, 2013; Walker & LeVine 2012), regardless of whether the seed is exogenous or endogenous in origin.”
BackgroundSelf-citationSporadic human prion diseases: molecular insights and diagnosis
Puoti, G., Bizzi, A., Forloni, G., Safar, J., Tagliavini, F., & Gambetti, P. L. (2012) · The Lancet Neurology · doi:10.1016/s1474-4422(12)70063-7 · Cited by 362 · see citing works
Rüb, U., Schöls, L. J., Paulson, H. L., Auburger, G. W. J., Kermer, P., Jen, J. C., Seidel, K., Korf, H., & Deller, T. (2013) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2013.01.001 · Cited by 338 · see citing works
The cerebellum in Alzheimer’s disease: evaluating its role in cognitive decline
Jacobs, H. I. L., Hopkins, D. A., Mayrhofer, H. C., Bruner, E., van Leeuwen, F. W., Raaijmakers, W., & Schmahmann, J. D. (2017) · Brain · doi:10.1093/brain/awx194 · Cited by 339 · see citing works
“The locus coeruleus has been postulated to be the initial site of tau pathology, which may potentiate amyloid pathology (Braak et al. , 2011; Jucker and Walker, 2011; Braak and Del Tredici, 2012; Jacobs et al. , 2014; Brettschneider et al. , 2015; Theofilas et al. , 2017).”
Long Road to Ruin: Noradrenergic Dysfunction in Neurodegenerative Disease
Weinshenker, D. (2018) · Trends in Neurosciences · doi:10.1016/j.tins.2018.01.010 · Cited by 323 · see citing works
“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].”
Pandi-Perumal, S. R., BaHammam, A. S., Brown, G. M., Spence, D. W., Bharti, V. K., Kaur, C., Hardeland, R., & Cardinali, D. P. (2012) · Neurotoxicity Research · doi:10.1007/s12640-012-9337-4 · Cited by 320 · see citing works
“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 · see citing works
“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 · see citing works
“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 307 · see citing works
“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 295 · see citing works
“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 · see citing works
Govindpani, K., McNamara, L. G., Smith, N. R., Vinnakota, C., Waldvogel, H. J., Faull, R. L. M., & Kwakowsky, A. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8050651 · Cited by 271 · see citing works
“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 274 · see citing works
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 252 · see citing works
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 · see citing works
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 258 · see citing works
(2012) · PubMed Central · Cited by 248 · see citing works
Structure and Aggregation Mechanisms in Amyloids
Almeida, Z. L., & Brito, R. M. M. (2020) · Molecules · doi:10.3390/molecules25051195 · Cited by 248 · see citing works
Deleault, N. R., Piro, J. R., Walsh, D. J., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1204498109 · Cited by 247 · see citing works
“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 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
Morales, R., Moreno‐González, I., & Soto, C. A. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003537 · Cited by 220 · see citing works
“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 213 · see citing works
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 · see citing works
“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 203 · see citing works
Moreno‐González, I., Edwards, G. A., Salvadores, N., Shahnawaz, M., Díaz‐Espinoza, R., & Soto, C. A. (2017) · Molecular Psychiatry · doi:10.1038/mp.2016.230 · Cited by 210 · see citing works
“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 206 · see citing works
“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 · see citing works
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 · see citing works
“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., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1206999109 · Cited by 187 · see citing works
“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 187 · see citing works
“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 189 · see citing works
“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 · see citing works
“…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 182 · see citing works
“…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 174 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
“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 158 · see citing works
Leuner, K., Müller, W. E., & Reichert, A. S. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8307-4 · Cited by 155 · see citing works
“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 156 · see citing works
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 160 · see citing works
Costanzo, M., & Zurzolo, C. (2013) · Biochemical Journal · doi:10.1042/bj20121898 · Cited by 151 · see citing works
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 · see citing works
“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 · see citing works
“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.”
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 · see citing works
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 · see citing works
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 142 · see citing works
Haass, C., & Selkoe, D. (2022) · PLOS Biology · doi:10.1371/journal.pbio.3001694 · Cited by 145 · see citing works
“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].”
BackgroundCurrent and emerging avenues for Alzheimer's disease drug targets
Loera‐Valencia, R., Cedazo-Mı́nguez, 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 139 · see citing works
Traumatic brain injury: a risk factor for neurodegenerative diseases
Gupta, R. K., & Sen, N. (2016) · Reviews in the Neurosciences · doi:10.1515/revneuro-2015-0017 · Cited by 116 · see citing works
“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 139 · see citing works
“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 137 · see citing works
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 136 · see citing works
“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 137 · see citing works
Bernardelli, A., Chiasserini, D., Biscetti, L., Eusebi, P., Salvadori, N., Frattini, G., Simoni, S., de Roeck, N., Tambasco, N., Stoops, E., et al. (2017) · Alzheimer's Research & Therapy · doi:10.1186/s13195-017-0276-4 · Cited by 128 · see citing works
“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 135 · see citing works
α1-Adrenergic Receptors in Neurotransmission, Synaptic Plasticity, and Cognition
Perez, D. M. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.581098 · Cited by 131 · see citing works
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 · see citing works
“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 135 · see citing works
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 129 · see citing works
“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 128 · see citing works
“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 129 · see citing works
Burke, K. A., Yates, E. A., & Legleiter, J. (2013) · Frontiers in Neurology · doi:10.3389/fneur.2013.00017 · Cited by 127 · see citing works
“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 · see citing works
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 · see citing works
Lo, A. C., Callaerts-Vegh, Z., Nunes, A. F., Rodrigues, C. M. P., & D'Hooge, R. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2012.09.003 · Cited by 120 · see citing works
“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 124 · see citing works
“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 121 · see citing works
“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 122 · see citing works
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 121 · see citing works
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 · see citing works
Norepinephrine metabolite DOPEGAL activates AEP and pathological Tau aggregation in locus coeruleus
Kang, S. S., Liu, X., Ahn, E. H., Xiang, J., Manfredsson, F. P., Yang, X., Luo, H. R., Liles, L. C., Weinshenker, D., & Ye, K. (2019) · Journal of Clinical Investigation · doi:10.1172/jci130513 · Cited by 117 · see citing works
“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 · see citing works
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 119 · see citing works
“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 · see citing works
Nussbaum, J. M., Seward, M. E., & Bloom, G. S. (2013) · Prion · doi:10.4161/pri.22118 · Cited by 117 · see citing works
- 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
- Health Sciences › Medicine › Physiology › 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
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