Soluble tau aggregates, not large fibrils, are the toxic species that display seeding and cross-seeding behavior

Gaurav Ghag, Nemil Bhatt, Daniel V. Cantu, Marcos J. Guerrero-Munoz, Anna Ellsworth, Urmi Sengupta, Rakez Kayed

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Several studies have proposed that fibrillary aggregates of tau and other amyloidogenic proteins are neurotoxic and result in numerous neurodegenerative diseases. However, these studies usually involve sonication or extrusion through needles before experimentation. As a consequence, these methods may fragment large aggregates producing a mixture of aggregated species rather than intact fibrils. Therefore, the results of these experiments may be reflective of other amyloidogenic species, such as oligomers and/or protofibrils/short fibrils. To investigate the effects of sonication on the aggregation of tau and other amyloidogenic proteins, fibrils were prepared and well characterized, then sonicated and evaluated by various biochemical and biophysical methods to identify the aggregated species present. We found that indeed a mixture of aggregated species was present along with short fibrils indicating that sonication leads to impure fibril samples and should be analyzed with caution. Our results corroborate the previous studies showing that sonication of prion and Aβ fibrils leads to the formation of toxic, soluble aggregates. We also show that the oligomeric forms are the most toxic species although it is unclear how sonication causes oligomer formation. Recent results suggest that these small toxic oligomers produced by sonication, rather than the stable fibrillar structures, are prion-like in nature displaying seeding and cross-seeding behavior.

Original languageEnglish (US)
Pages (from-to)1901-1909
Number of pages9
JournalProtein Science
Volume27
Issue number11
DOIs
StatePublished - Nov 1 2018

Fingerprint

Sonication
Poisons
Oligomers
Amyloidogenic Proteins
Prions
Neurodegenerative diseases
Neurodegenerative Diseases
Needles
Extrusion
Agglomeration
Experiments

Keywords

  • amyloid
  • sonication
  • tau oligomers
  • tauopathies

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this

Ghag, G., Bhatt, N., Cantu, D. V., Guerrero-Munoz, M. J., Ellsworth, A., Sengupta, U., & Kayed, R. (2018). Soluble tau aggregates, not large fibrils, are the toxic species that display seeding and cross-seeding behavior. Protein Science, 27(11), 1901-1909. https://doi.org/10.1002/pro.3499

Soluble tau aggregates, not large fibrils, are the toxic species that display seeding and cross-seeding behavior. / Ghag, Gaurav; Bhatt, Nemil; Cantu, Daniel V.; Guerrero-Munoz, Marcos J.; Ellsworth, Anna; Sengupta, Urmi; Kayed, Rakez.

In: Protein Science, Vol. 27, No. 11, 01.11.2018, p. 1901-1909.

Research output: Contribution to journalArticle

Ghag, G, Bhatt, N, Cantu, DV, Guerrero-Munoz, MJ, Ellsworth, A, Sengupta, U & Kayed, R 2018, 'Soluble tau aggregates, not large fibrils, are the toxic species that display seeding and cross-seeding behavior', Protein Science, vol. 27, no. 11, pp. 1901-1909. https://doi.org/10.1002/pro.3499
Ghag G, Bhatt N, Cantu DV, Guerrero-Munoz MJ, Ellsworth A, Sengupta U et al. Soluble tau aggregates, not large fibrils, are the toxic species that display seeding and cross-seeding behavior. Protein Science. 2018 Nov 1;27(11):1901-1909. https://doi.org/10.1002/pro.3499
Ghag, Gaurav ; Bhatt, Nemil ; Cantu, Daniel V. ; Guerrero-Munoz, Marcos J. ; Ellsworth, Anna ; Sengupta, Urmi ; Kayed, Rakez. / Soluble tau aggregates, not large fibrils, are the toxic species that display seeding and cross-seeding behavior. In: Protein Science. 2018 ; Vol. 27, No. 11. pp. 1901-1909.
@article{7c5e2b5775a54d3d84ec79964794bd58,
title = "Soluble tau aggregates, not large fibrils, are the toxic species that display seeding and cross-seeding behavior",
abstract = "Several studies have proposed that fibrillary aggregates of tau and other amyloidogenic proteins are neurotoxic and result in numerous neurodegenerative diseases. However, these studies usually involve sonication or extrusion through needles before experimentation. As a consequence, these methods may fragment large aggregates producing a mixture of aggregated species rather than intact fibrils. Therefore, the results of these experiments may be reflective of other amyloidogenic species, such as oligomers and/or protofibrils/short fibrils. To investigate the effects of sonication on the aggregation of tau and other amyloidogenic proteins, fibrils were prepared and well characterized, then sonicated and evaluated by various biochemical and biophysical methods to identify the aggregated species present. We found that indeed a mixture of aggregated species was present along with short fibrils indicating that sonication leads to impure fibril samples and should be analyzed with caution. Our results corroborate the previous studies showing that sonication of prion and Aβ fibrils leads to the formation of toxic, soluble aggregates. We also show that the oligomeric forms are the most toxic species although it is unclear how sonication causes oligomer formation. Recent results suggest that these small toxic oligomers produced by sonication, rather than the stable fibrillar structures, are prion-like in nature displaying seeding and cross-seeding behavior.",
keywords = "amyloid, sonication, tau oligomers, tauopathies",
author = "Gaurav Ghag and Nemil Bhatt and Cantu, {Daniel V.} and Guerrero-Munoz, {Marcos J.} and Anna Ellsworth and Urmi Sengupta and Rakez Kayed",
year = "2018",
month = "11",
day = "1",
doi = "10.1002/pro.3499",
language = "English (US)",
volume = "27",
pages = "1901--1909",
journal = "Protein Science",
issn = "0961-8368",
publisher = "Cold Spring Harbor Laboratory Press",
number = "11",

}

TY - JOUR

T1 - Soluble tau aggregates, not large fibrils, are the toxic species that display seeding and cross-seeding behavior

AU - Ghag, Gaurav

AU - Bhatt, Nemil

AU - Cantu, Daniel V.

AU - Guerrero-Munoz, Marcos J.

AU - Ellsworth, Anna

AU - Sengupta, Urmi

AU - Kayed, Rakez

PY - 2018/11/1

Y1 - 2018/11/1

N2 - Several studies have proposed that fibrillary aggregates of tau and other amyloidogenic proteins are neurotoxic and result in numerous neurodegenerative diseases. However, these studies usually involve sonication or extrusion through needles before experimentation. As a consequence, these methods may fragment large aggregates producing a mixture of aggregated species rather than intact fibrils. Therefore, the results of these experiments may be reflective of other amyloidogenic species, such as oligomers and/or protofibrils/short fibrils. To investigate the effects of sonication on the aggregation of tau and other amyloidogenic proteins, fibrils were prepared and well characterized, then sonicated and evaluated by various biochemical and biophysical methods to identify the aggregated species present. We found that indeed a mixture of aggregated species was present along with short fibrils indicating that sonication leads to impure fibril samples and should be analyzed with caution. Our results corroborate the previous studies showing that sonication of prion and Aβ fibrils leads to the formation of toxic, soluble aggregates. We also show that the oligomeric forms are the most toxic species although it is unclear how sonication causes oligomer formation. Recent results suggest that these small toxic oligomers produced by sonication, rather than the stable fibrillar structures, are prion-like in nature displaying seeding and cross-seeding behavior.

AB - Several studies have proposed that fibrillary aggregates of tau and other amyloidogenic proteins are neurotoxic and result in numerous neurodegenerative diseases. However, these studies usually involve sonication or extrusion through needles before experimentation. As a consequence, these methods may fragment large aggregates producing a mixture of aggregated species rather than intact fibrils. Therefore, the results of these experiments may be reflective of other amyloidogenic species, such as oligomers and/or protofibrils/short fibrils. To investigate the effects of sonication on the aggregation of tau and other amyloidogenic proteins, fibrils were prepared and well characterized, then sonicated and evaluated by various biochemical and biophysical methods to identify the aggregated species present. We found that indeed a mixture of aggregated species was present along with short fibrils indicating that sonication leads to impure fibril samples and should be analyzed with caution. Our results corroborate the previous studies showing that sonication of prion and Aβ fibrils leads to the formation of toxic, soluble aggregates. We also show that the oligomeric forms are the most toxic species although it is unclear how sonication causes oligomer formation. Recent results suggest that these small toxic oligomers produced by sonication, rather than the stable fibrillar structures, are prion-like in nature displaying seeding and cross-seeding behavior.

KW - amyloid

KW - sonication

KW - tau oligomers

KW - tauopathies

UR - http://www.scopus.com/inward/record.url?scp=85055245559&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85055245559&partnerID=8YFLogxK

U2 - 10.1002/pro.3499

DO - 10.1002/pro.3499

M3 - Article

VL - 27

SP - 1901

EP - 1909

JO - Protein Science

JF - Protein Science

SN - 0961-8368

IS - 11

ER -