Characterization by atomic force microscopy and cryoelectron microscopy of tau polymers assembled in Alzheimer's disease1

Moreno‐Herrero, Fernando; Valpuesta, José; Pérez, Mar; Colchero, J.; Baró, A. M.; Ávila, Jesús; Garcini, Esteban Montejo de

doi:10.3233/jad-2001-3502

Cited by 14 publications

(25 citation statements)

References 49 publications

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“…Comparing the periodicity and thickness of thick Tau fibrils characterized here by AFM with the periodicity of ϳ80 nm and width of ϳ22 nm reported for PHFs by EM (13,14), it may be concluded that the thick Tau fibrils reflect the commonly reported PHF structure. This interpretation would be in agreement with previous AFM studies (17,35). However, the coexistence of thin smooth, thin corrugated, and thick fibrils reassembled from the same Tau proteins suggests that these different structural classes may be gathered from Tau proteins showing different assemblies or conformations.…”

Section: Tau Proteins Assemble Into Polymorphoussupporting

confidence: 93%

Human Tau Isoforms Assemble into Ribbon-like Fibrils That Display Polymorphic Structure and Stability

Wegmann

Jung

Chinnathambi

et al. 2010

Journal of Biological Chemistry

101

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Fibrous aggregates of Tau protein are characteristic features of Alzheimer disease. We applied high resolution atomic force and EM microscopy to study fibrils assembled from different human Tau isoforms and domains. All fibrils reveal structural polymorphism; the "thin twisted" and "thin smooth" fibrils resemble flat ribbons (cross-section ϳ10 ؋ 15 nm) with diverse twist periodicities. "Thick fibrils" show periodicities of ϳ65-70 nm and thicknesses of ϳ9 -18 nm such as routinely reported for "paired helical filaments" but structurally resemble heavily twisted ribbons. Therefore, thin and thick fibrils assembled from different human Tau isoforms challenge current structural models of paired helical filaments. Furthermore, all Tau fibrils reveal axial subperiodicities of ϳ17-19 nm and, upon exposure to mechanical stress or hydrophobic surfaces, disassemble into uniform fragments that remain connected by thin thread-like structures (ϳ2 nm). This hydrophobically induced disassembly is inhibited at enhanced electrolyte concentrations, indicating that the fragments resemble structural building blocks and the fibril integrity depends largely on hydrophobic and electrostatic interactions. Because full-length Tau and repeat domain constructs assemble into fibrils of similar thickness, the "fuzzy coat" of Tau protein termini surrounding the fibril axis is nearly invisible for atomic force microscopy and EM, presumably because of its high flexibility.

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Section: Tau Proteins Assemble Into Polymorphoussupporting

confidence: 93%

Human Tau Isoforms Assemble into Ribbon-like Fibrils That Display Polymorphic Structure and Stability

Wegmann

Jung

Chinnathambi

et al. 2010

Journal of Biological Chemistry

101

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“…In summary, our results obtained with acrolein and methylglyoxal suggest that the formation of covalently linked dimers, trimers, or tetramers may be an important step in filament assembly (17,55,56). Consistent with such a suggestion, a Tau tetramer was previously suggested as the smallest building block of AD-derived PHFs when PHF images were analyzed quantitatively from atomic force microscopy and electron microscopy (54).…”

Section: Microscopic Fibrilssupporting

confidence: 63%

“…6) show some resemblance to PHFs isolated from AD brains (1). These AD filaments are ϳ530 nm long with characteristic subunits of ϳ16 ϫ 82 nm (54). However, our synthetic filaments are similar but are straight and lack the twisted appearance of the PHF isolated in vivo.…”

Section: Microscopic Fibrilsmentioning

confidence: 71%

Effect of Pseudophosphorylation and Cross-linking by Lipid Peroxidation and Advanced Glycation End Product Precursors on Tau Aggregation and Filament Formation

Kuhla¹,

Haase

Flach

et al. 2007

Journal of Biological Chemistry

104

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Accumulation of hyperphosphorylated Tau protein as paired helical filaments in pyramidal neurons is a major hallmark of Alzheimer disease. Besides hyperphosphorylation, other modifications of the Tau protein, such as cross-linking, are likely to contribute to the characteristic features of paired helical filaments, including their insolubility and resistance against proteolytic degradation. In this study, we have investigated whether the four reactive carbonyl compounds acrolein, malondialdehyde, glyoxal, and methylglyoxal accelerate the formation of Tau oligomers, thioflavin T-positive aggregates, and fibrils using wild-type and seven pseudophosphorylated mutant Tau proteins. Acrolein and methylglyoxal were the most reactive compounds followed by glyoxal and malondialdehyde in terms of formation of Tau dimers and higher molecular weight oligomers. Furthermore, acrolein and methylglyoxal induced the formation of thioflavin T-fluorescent aggregates in a triple pseudophosphorylation-mimicking mutant to a slightly higher degree than wild-type Tau. Analysis of the Tau aggregates by electron microscopy study showed that formation of fibrils using wild-type Tau and several Tau mutants could be observed with acrolein and methylglyoxal but not with glyoxal and malondialdehyde. Our results suggest that reactive carbonyl compounds, particularly methylglyoxal and acrolein, could accelerate tangle formation in vivo and that this process could be slightly accelerated, at least in the case of methylglyoxal and acrolein, by hyperphosphorylation. Interference with the formation or the reaction of these reactive carbonyl compounds could be a promising way of inhibiting tangle formation and neuronal dysfunction in Alzheimer disease and other tauopathies.

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“…The beads on a string morphology of the filaments revealed by AFM is in contrast with the morphology of other filament-like structures found in other neurodegenerative diseases like the paired helical filaments isolated from Alzheimer's disease patients, which present a clear helical and ribbon-like morphology (Pollanen et al, 1994;Moreno-Herrero et al, 2001. However, the beads on a string morphology of the here purified filaments is identical to that reported after in vitro assembling of recombinant exon 1 mutant htt (Poirier et al, 2002) and very similar to those generated by other amyloidogenic proteins such as A␤, ␣-synuclein, and yeast (prion) Sup35 NM peptide (Harper et al, 1999;Rochet et al, 2000).…”

Section: Discussionmentioning

confidence: 69%

“…The sample was washed with deionized and double-distilled water, dried with nitrogen gas, and imaged in air with a commercial microscope (Nanotec Electronica, Madrid, Spain) operating in noncontact dynamic mode as previously described (Moreno-Herrero et al, 2001. Images were processed using WSxM freeware.…”

Section: Atomic Force Microscopy Of Purified Aggregatesmentioning

confidence: 99%

Biochemical, Ultrastructural, and Reversibility Studies on Huntingtin Filaments Isolated from Mouse and Human Brain

et al. 2004

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Huntington's disease (HD) and eight additional inherited neurological disorders are caused by CAG triplet-repeat expansions leading to expanded polyglutamine-sequences in their respective proteins. These triplet-CAG repeat disorders have in common the formation of aberrant intraneuronal proteinaceous inclusions containing the expanded polyglutamine sequences. These aggregates have been postulated to contribute to pathogenesis caused by conformational toxicity, sequestration of other polyglutamine-containing proteins, or by interfering with certain enzymatic activities. Testing these hypotheses has been hampered by the difficulty to isolate these aggregates from brain. Here we report that polyglutamine aggregates can be isolated from the brain of the Tet/HD94 conditional mouse model of HD, by following a method based on high salt buffer homogenization, nonionic detergent extraction, and gradient fractionation. We then verified that the method can be successfully applied to postmortem HD brains. Immunoelectron microscopy, both in human and mouse samples, revealed that the stable component of the inclusions are mutant huntingtin-containing and ubiquitin-containing fibrils. Atomic-force microscopy revealed that these fibrils have a "beads on a string" morphology. Thus, they resemble the in vitro assembled filaments made of recombinant mutant-huntingtin, as well as the A␤ and ␣-synuclein amyloid protofibrils. Finally, by shutting down transgene expression in the Tet/HD94 conditional mouse model of HD, we were able to demonstrate that these filaments, although stable in vitro, are susceptible to revert in vivo, thus demonstrating that the previously reported reversal of ubiquitin-immunoreactive inclusions does not simply reflect disassembling of the inclusions into their constituent fibrils and suggesting that any associated conformational or protein-sequestration toxicity is also likely to revert.

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Characterization by atomic force microscopy and cryoelectron microscopy of tau polymers assembled in Alzheimer's disease1

Cited by 14 publications

References 49 publications

Human Tau Isoforms Assemble into Ribbon-like Fibrils That Display Polymorphic Structure and Stability

Human Tau Isoforms Assemble into Ribbon-like Fibrils That Display Polymorphic Structure and Stability

Effect of Pseudophosphorylation and Cross-linking by Lipid Peroxidation and Advanced Glycation End Product Precursors on Tau Aggregation and Filament Formation

Biochemical, Ultrastructural, and Reversibility Studies on Huntingtin Filaments Isolated from Mouse and Human Brain

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