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Title: Amyloid structure exhibits polymorphism on multiple length scales in human brain tissue

Abstract

Although aggregation of Aβ amyloid fibrils into plaques in the brain is a hallmark of Alzheimer's Disease (AD), the correlation between amyloid burden and severity of symptoms is weak. One possible reason is that amyloid fibrils are structurally polymorphic and different polymorphs may contribute differentially to disease. However, the occurrence and distribution of amyloid polymorphisms in human brain is poorly documented. Here we seek to fill this knowledge gap by using X-ray microdiffraction of histological sections of human tissue to map the abundance, orientation and structural heterogeneities of amyloid within individual plaques; among proximal plaques and in subjects with distinct clinical histories. A 5 µ x-ray beam was used to generate diffraction data with each pattern arising from a scattering volume of only ~ 450 µ3 , making possible collection of dozens to hundreds of diffraction patterns from a single amyloid plaque. X-ray scattering from these samples exhibited all the properties expected for scattering from amyloid. Amyloid distribution was mapped using the intensity of its signature 4.7 Å reflection which also provided information on the orientation of amyloid fibrils across plaques. Margins of plaques exhibited a greater degree of orientation than cores and orientation around blood vessels frequently appeared tangential.more » Variation in the structure of Aβ fibrils is reflected in the shape of the 4.7 Å peak which usually appears as a doublet. Variations in this peak correspond to differences between the structure of amyloid within cores of plaques and at their periphery. Examination of tissue from a mismatch case - an individual with high plaque burden but no overt signs of dementia at time of death - revealed a diversity of structure and spatial distribution of amyloid that is distinct from typical AD cases. As a result, we demonstrate the existence of structural polymorphisms among amyloid within and among plaques of a single individual and suggest the existence of distinct differences in the organization of amyloid in subjects with different clinical presentations.« less

Authors:
 [1];  [2];  [3];  [3];  [2];  [2];  [2];  [1]
  1. Northeastern Univ., Boston, MA (United States)
  2. Massachusetts General Hospital, Boston, MA (United States)
  3. Argonne National Lab. (ANL), Argonne, IL (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Institutes of Health (NIH)
OSTI Identifier:
1341005
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Accepted Manuscript
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Volume: 6; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; diseases of the nervous system; molecular biophysics

Citation Formats

Liu, Jiliang, Costantino, Isabel, Venugopalan, Nagarajan, Fischetti, Robert F., Hyman, Bradley T., Frosch, Matthew P., Gomez-Isla, Teresa, and Makowski, Lee. Amyloid structure exhibits polymorphism on multiple length scales in human brain tissue. United States: N. p., 2016. Web. doi:10.1038/srep33079.
Liu, Jiliang, Costantino, Isabel, Venugopalan, Nagarajan, Fischetti, Robert F., Hyman, Bradley T., Frosch, Matthew P., Gomez-Isla, Teresa, & Makowski, Lee. Amyloid structure exhibits polymorphism on multiple length scales in human brain tissue. United States. https://doi.org/10.1038/srep33079
Liu, Jiliang, Costantino, Isabel, Venugopalan, Nagarajan, Fischetti, Robert F., Hyman, Bradley T., Frosch, Matthew P., Gomez-Isla, Teresa, and Makowski, Lee. Thu . "Amyloid structure exhibits polymorphism on multiple length scales in human brain tissue". United States. https://doi.org/10.1038/srep33079. https://www.osti.gov/servlets/purl/1341005.
@article{osti_1341005,
title = {Amyloid structure exhibits polymorphism on multiple length scales in human brain tissue},
author = {Liu, Jiliang and Costantino, Isabel and Venugopalan, Nagarajan and Fischetti, Robert F. and Hyman, Bradley T. and Frosch, Matthew P. and Gomez-Isla, Teresa and Makowski, Lee},
abstractNote = {Although aggregation of Aβ amyloid fibrils into plaques in the brain is a hallmark of Alzheimer's Disease (AD), the correlation between amyloid burden and severity of symptoms is weak. One possible reason is that amyloid fibrils are structurally polymorphic and different polymorphs may contribute differentially to disease. However, the occurrence and distribution of amyloid polymorphisms in human brain is poorly documented. Here we seek to fill this knowledge gap by using X-ray microdiffraction of histological sections of human tissue to map the abundance, orientation and structural heterogeneities of amyloid within individual plaques; among proximal plaques and in subjects with distinct clinical histories. A 5 µ x-ray beam was used to generate diffraction data with each pattern arising from a scattering volume of only ~ 450 µ3 , making possible collection of dozens to hundreds of diffraction patterns from a single amyloid plaque. X-ray scattering from these samples exhibited all the properties expected for scattering from amyloid. Amyloid distribution was mapped using the intensity of its signature 4.7 Å reflection which also provided information on the orientation of amyloid fibrils across plaques. Margins of plaques exhibited a greater degree of orientation than cores and orientation around blood vessels frequently appeared tangential. Variation in the structure of Aβ fibrils is reflected in the shape of the 4.7 Å peak which usually appears as a doublet. Variations in this peak correspond to differences between the structure of amyloid within cores of plaques and at their periphery. Examination of tissue from a mismatch case - an individual with high plaque burden but no overt signs of dementia at time of death - revealed a diversity of structure and spatial distribution of amyloid that is distinct from typical AD cases. As a result, we demonstrate the existence of structural polymorphisms among amyloid within and among plaques of a single individual and suggest the existence of distinct differences in the organization of amyloid in subjects with different clinical presentations.},
doi = {10.1038/srep33079},
journal = {Scientific Reports},
number = ,
volume = 6,
place = {United States},
year = {Thu Sep 15 00:00:00 EDT 2016},
month = {Thu Sep 15 00:00:00 EDT 2016}
}

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Works referenced in this record:

Resolving controversies on the path to Alzheimer's therapeutics
journal, September 2011


The toxic Aβ oligomer and Alzheimer's disease: an emperor in need of clothes
journal, January 2012

  • Benilova, Iryna; Karran, Eric; De Strooper, Bart
  • Nature Neuroscience, Vol. 15, Issue 3
  • DOI: 10.1038/nn.3028

Tangles and plaques in nondemented aging and ?preclinical? Alzheimer's disease
journal, March 1999


Identification of normal and pathological aging in prospectively studied nondemented elderly humans
journal, January 1992


Multimodal techniques for diagnosis and prognosis of Alzheimer's disease
journal, October 2009

  • Perrin, Richard J.; Fagan, Anne M.; Holtzman, David M.
  • Nature, Vol. 461, Issue 7266
  • DOI: 10.1038/nature08538

In the beginning ...
journal, December 1991


Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory
journal, June 2008

  • Shankar, Ganesh M.; Li, Shaomin; Mehta, Tapan H.
  • Nature Medicine, Vol. 14, Issue 8
  • DOI: 10.1038/nm1782

Amyloid pores from pathogenic mutations
journal, July 2002

  • Lashuel, Hilal A.; Hartley, Dean; Petre, Benjamin M.
  • Nature, Vol. 418, Issue 6895
  • DOI: 10.1038/418291a

Amyloid Polymorphism: Structural Basis and Neurobiological Relevance
journal, May 2015


Molecular Structure of β-Amyloid Fibrils in Alzheimer’s Disease Brain Tissue
journal, September 2013


Dissecting phenotypic traits linked to human resilience to Alzheimer’s pathology
journal, July 2013

  • Perez-Nievas, Beatriz G.; Stein, Thor D.; Tai, Hwan-Ching
  • Brain, Vol. 136, Issue 8
  • DOI: 10.1093/brain/awt171

Molecular basis for amyloid-  polymorphism
journal, September 2011

  • Colletier, J. -P.; Laganowsky, A.; Landau, M.
  • Proceedings of the National Academy of Sciences, Vol. 108, Issue 41
  • DOI: 10.1073/pnas.1112600108

Peptide dimer structure in an Aβ(1–42) fibril visualized with cryo-EM
journal, September 2015

  • Schmidt, Matthias; Rohou, Alexis; Lasker, Keren
  • Proceedings of the National Academy of Sciences, Vol. 112, Issue 38
  • DOI: 10.1073/pnas.1503455112

Observation of metastable Aβ amyloid protofibrils by atomic force microscopy
journal, January 1997


Multiple Assembly Pathways Underlie Amyloid-β Fibril Polymorphisms
journal, September 2005

  • Goldsbury, Claire; Frey, Peter; Olivieri, Vesna
  • Journal of Molecular Biology, Vol. 352, Issue 2
  • DOI: 10.1016/j.jmb.2005.07.029

Aβ(1-40) Fibril Polymorphism Implies Diverse Interaction Patterns in Amyloid Fibrils
journal, February 2009

  • Meinhardt, Jessica; Sachse, Carsten; Hortschansky, Peter
  • Journal of Molecular Biology, Vol. 386, Issue 3
  • DOI: 10.1016/j.jmb.2008.11.005

Review: Modulating Factors in Amyloid-β Fibril Formation
journal, June 2000

  • McLaurin, J.; Yang, D. -S.; Yip, C. M.
  • Journal of Structural Biology, Vol. 130, Issue 2-3
  • DOI: 10.1006/jsbi.2000.4289

Self-Propagating, Molecular-Level Polymorphism in Alzheimer's  -Amyloid Fibrils
journal, January 2005


Polymorph-Specific Kinetics and Thermodynamics of β-Amyloid Fibril Growth
journal, April 2013

  • Qiang, Wei; Kelley, Kevin; Tycko, Robert
  • Journal of the American Chemical Society, Vol. 135, Issue 18
  • DOI: 10.1021/ja311963f

Intrinsic Structural Heterogeneity and Long-Term Maturation of Amyloid β Peptide Fibrils
journal, May 2013

  • Ma, Jianqiang; Komatsu, Hiroaki; Kim, Yung Sam
  • ACS Chemical Neuroscience, Vol. 4, Issue 8
  • DOI: 10.1021/cn400092v

Evidence for Age-Dependent in Vivo Conformational Rearrangement within Aβ Amyloid Deposits
journal, March 2013

  • Nyström, Sofie; Psonka-Antonczyk, Katarzyna M.; Ellingsen, Pål Gunnar
  • ACS Chemical Biology, Vol. 8, Issue 6
  • DOI: 10.1021/cb4000376

A Template for New Drugs against Alzheimer’s Disease
journal, September 2013


X-Ray Diffraction Studies on Amyloid Filaments
journal, November 1968

  • Eanes, E. D.; Glenner, G. G.
  • Journal of Histochemistry & Cytochemistry, Vol. 16, Issue 11
  • DOI: 10.1177/16.11.673

Alzheimer’s amyloid fibrils: structure and assembly
journal, July 2000


Synthetic peptide homologous to beta protein from Alzheimer disease forms amyloid-like fibrils in vitro.
journal, October 1987

  • Kirschner, D. A.; Inouye, H.; Duffy, L. K.
  • Proceedings of the National Academy of Sciences, Vol. 84, Issue 19
  • DOI: 10.1073/pnas.84.19.6953

X-ray Diffraction of Scrapie Prion Rods and PrP Peptides
journal, September 1995

  • Nguyen, Jack T.; Inouye, Hideyo; Baldwin, Michael A.
  • Journal of Molecular Biology, Vol. 252, Issue 4
  • DOI: 10.1006/jmbi.1995.0507

Natural and synthetic prion structure from X-ray fiber diffraction
journal, September 2009

  • Wille, H.; Bian, W.; McDonald, M.
  • Proceedings of the National Academy of Sciences, Vol. 106, Issue 40
  • DOI: 10.1073/pnas.0909006106

Common core structure of amyloid fibrils by synchrotron X-ray diffraction 1 1Edited by F. E. Cohen
journal, October 1997

  • Sunde, Margaret; Serpell, Louise C.; Bartlam, Mark
  • Journal of Molecular Biology, Vol. 273, Issue 3
  • DOI: 10.1006/jmbi.1997.1348

Evidence for Novel β-Sheet Structures in Iowa Mutant β-Amyloid Fibrils
journal, July 2009

  • Tycko, Robert; Sciarretta, Kimberly L.; Orgel, Joseph P. R. O.
  • Biochemistry, Vol. 48, Issue 26
  • DOI: 10.1021/bi9002666

Fiber Diffraction Data Indicate a Hollow Core for the Alzheimer's Aβ 3-Fold Symmetric Fibril
journal, October 2012


The Common Architecture of Cross-β Amyloid
journal, January 2010

  • Jahn, Thomas R.; Makin, O. Sumner; Morris, Kyle L.
  • Journal of Molecular Biology, Vol. 395, Issue 4
  • DOI: 10.1016/j.jmb.2009.09.039

X-ray Scattering Study of the Effect of Hydration on the Cross-β Structure of Amyloid Fibrils
journal, September 2006

  • Squires, Adam M.; Devlin, Glyn L.; Gras, Sally L.
  • Journal of the American Chemical Society, Vol. 128, Issue 36
  • DOI: 10.1021/ja063751v

Conformation of twisted β-pleated sheets in proteins
journal, April 1973


Structural properties of protein β-sheets
journal, January 1983


Structure of beta-crystallite assemblies formed by Alzheimer beta-amyloid protein analogues: analysis by x-ray diffraction
journal, February 1993


Synchrotron X-Ray Microdiffraction Reveals Intrinsic Structural Features of Amyloid Deposits In Situ
journal, July 2011


Imaging linear birefringence and dichroism in cerebral amyloid pathologies
journal, December 2003

  • Jin, L. -W.; Claborn, K. A.; Kurimoto, M.
  • Proceedings of the National Academy of Sciences, Vol. 100, Issue 26
  • DOI: 10.1073/pnas.2534647100

Imaging Distinct Conformational States of Amyloid-β Fibrils in Alzheimer’s Disease Using Novel Luminescent Probes
journal, August 2007

  • Nilsson, K. Peter R.; Åslund, Andreas; Berg, Ina
  • ACS Chemical Biology, Vol. 2, Issue 8
  • DOI: 10.1021/cb700116u

Molecular structural basis for polymorphism in Alzheimer's  -amyloid fibrils
journal, November 2008

  • Paravastu, A. K.; Leapman, R. D.; Yau, W. -M.
  • Proceedings of the National Academy of Sciences, Vol. 105, Issue 47
  • DOI: 10.1073/pnas.0806270105

Serial propagation of distinct strains of A  prions from Alzheimer's disease patients
journal, June 2014

  • Watts, J. C.; Condello, C.; Stohr, J.
  • Proceedings of the National Academy of Sciences, Vol. 111, Issue 28
  • DOI: 10.1073/pnas.1408900111

Distinct synthetic A  prion strains producing different amyloid deposits in bigenic mice
journal, June 2014

  • Stohr, J.; Condello, C.; Watts, J. C.
  • Proceedings of the National Academy of Sciences, Vol. 111, Issue 28
  • DOI: 10.1073/pnas.1408968111

A template for new drugs against Alzheimer's Disease
text, January 2013


X-ray Diffraction of Scrapie Prion Rods and PrP Peptides
journal, September 1995

  • Nguyen, Jack T.; Inouye, Hideyo; Baldwin, Michael A.
  • Journal of Molecular Biology, Vol. 252, Issue 4
  • DOI: 10.1006/jmbi.1995.0507

Review: Modulating Factors in Amyloid-β Fibril Formation
journal, June 2000

  • McLaurin, J.; Yang, D. -S.; Yip, C. M.
  • Journal of Structural Biology, Vol. 130, Issue 2-3
  • DOI: 10.1006/jsbi.2000.4289

Binding of the dye congo red to the amyloid protein pig insulin reveals a novel homology amongst amyloid-forming peptide sequences
journal, October 1992


Synchrotron X-Ray Microdiffraction Reveals Intrinsic Structural Features of Amyloid Deposits In Situ
journal, July 2011


The Common Architecture of Cross-β Amyloid
journal, January 2010

  • Jahn, Thomas R.; Makin, O. Sumner; Morris, Kyle L.
  • Journal of Molecular Biology, Vol. 395, Issue 4
  • DOI: 10.1016/j.jmb.2009.09.039

Amyloid Polymorphism: Structural Basis and Neurobiological Relevance
journal, May 2015


Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein
journal, May 1984


A Model for Structure-Dependent Binding of Congo Red to Alzheimer β-Amyloid Fibrils
journal, January 1998


The morphological phenotype of β-amyloid plaques and associated neuritic changes in Alzheimer’s disease
journal, July 2001


Evidence for Age-Dependent in Vivo Conformational Rearrangement within Aβ Amyloid Deposits
journal, March 2013

  • Nyström, Sofie; Psonka-Antonczyk, Katarzyna M.; Ellingsen, Pål Gunnar
  • ACS Chemical Biology, Vol. 8, Issue 6
  • DOI: 10.1021/cb4000376

When Conjugated Polymers Meet Amyloid Fibrils
journal, August 2007

  • Stains, Cliff I.; Ghosh, Indraneel
  • ACS Chemical Biology, Vol. 2, Issue 8
  • DOI: 10.1021/cb700165v

Intrinsic Structural Heterogeneity and Long-Term Maturation of Amyloid β Peptide Fibrils
journal, May 2013

  • Ma, Jianqiang; Komatsu, Hiroaki; Kim, Yung Sam
  • ACS Chemical Neuroscience, Vol. 4, Issue 8
  • DOI: 10.1021/cn400092v

X-ray Scattering Study of the Effect of Hydration on the Cross-β Structure of Amyloid Fibrils
journal, September 2006

  • Squires, Adam M.; Devlin, Glyn L.; Gras, Sally L.
  • Journal of the American Chemical Society, Vol. 128, Issue 36
  • DOI: 10.1021/ja063751v

Multimodal techniques for diagnosis and prognosis of Alzheimer's disease
journal, October 2009

  • Perrin, Richard J.; Fagan, Anne M.; Holtzman, David M.
  • Nature, Vol. 461, Issue 7266
  • DOI: 10.1038/nature08538

Erratum: Corrigendum: Resolving controversies on the path to Alzheimer's therapeutics
journal, November 2011


Molecular structural basis for polymorphism in Alzheimer's  -amyloid fibrils
journal, November 2008

  • Paravastu, A. K.; Leapman, R. D.; Yau, W. -M.
  • Proceedings of the National Academy of Sciences, Vol. 105, Issue 47
  • DOI: 10.1073/pnas.0806270105

Natural and synthetic prion structure from X-ray fiber diffraction
journal, September 2009

  • Wille, H.; Bian, W.; McDonald, M.
  • Proceedings of the National Academy of Sciences, Vol. 106, Issue 40
  • DOI: 10.1073/pnas.0909006106

Molecular basis for amyloid-  polymorphism
journal, September 2011

  • Colletier, J. -P.; Laganowsky, A.; Landau, M.
  • Proceedings of the National Academy of Sciences, Vol. 108, Issue 41
  • DOI: 10.1073/pnas.1112600108

Serial propagation of distinct strains of A  prions from Alzheimer's disease patients
journal, June 2014

  • Watts, J. C.; Condello, C.; Stohr, J.
  • Proceedings of the National Academy of Sciences, Vol. 111, Issue 28
  • DOI: 10.1073/pnas.1408900111

Synthetic peptide homologous to beta protein from Alzheimer disease forms amyloid-like fibrils in vitro.
journal, October 1987

  • Kirschner, D. A.; Inouye, H.; Duffy, L. K.
  • Proceedings of the National Academy of Sciences, Vol. 84, Issue 19
  • DOI: 10.1073/pnas.84.19.6953

Intrinsic Linear Heterogeneity of Amyloid β Protein Fibrils Revealed by Higher Resolution Mass-per-length Determinations
journal, October 2010

  • Komatsu, Hiroaki; Feingold-Link, Elana; Sharp, Kim A.
  • Journal of Biological Chemistry, Vol. 285, Issue 53
  • DOI: 10.1074/jbc.m110.165068

Self-Propagating, Molecular-Level Polymorphism in Alzheimer's  -Amyloid Fibrils
journal, January 2005


X-Ray Diffraction Studies on Amyloid Filaments
journal, November 1968

  • Eanes, E. D.; Glenner, G. G.
  • Journal of Histochemistry & Cytochemistry, Vol. 16, Issue 11
  • DOI: 10.1177/16.11.673

Works referencing / citing this record:

Super‐Resolution Infrared Imaging of Polymorphic Amyloid Aggregates Directly in Neurons
journal, March 2020

  • Klementieva, Oxana; Sandt, Christophe; Martinsson, Isak
  • Advanced Science, Vol. 7, Issue 6
  • DOI: 10.1002/advs.201903004

Measurement of amyloid formation by turbidity assay—seeing through the cloud
journal, November 2016


Early Stage Alpha-Synuclein Amyloid Fibrils are Reservoirs of Membrane-Binding Species
journal, February 2019


Nanoscale structure of amyloid-β plaques in Alzheimer’s disease
journal, March 2019

  • Querol-Vilaseca, Marta; Colom-Cadena, Martí; Pegueroles, Jordi
  • Scientific Reports, Vol. 9, Issue 1
  • DOI: 10.1038/s41598-019-41443-3

Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer’s disease
journal, November 2017

  • Rasmussen, Jay; Mahler, Jasmin; Beschorner, Natalie
  • Proceedings of the National Academy of Sciences, Vol. 114, Issue 49
  • DOI: 10.1073/pnas.1713215114

Parkinson’s disease is a type of amyloidosis featuring accumulation of amyloid fibrils of α-synuclein
journal, August 2019

  • Araki, Katsuya; Yagi, Naoto; Aoyama, Koki
  • Proceedings of the National Academy of Sciences, Vol. 116, Issue 36
  • DOI: 10.1073/pnas.1906124116

X-ray diffraction reveals blunt-force loading threshold for nanoscopic structural change in ex vivo neuronal tissues
journal, January 2019

  • Orgel, Joseph; Madhurapantula, Rama S.; Eidsmore, Ashley
  • Journal of Synchrotron Radiation, Vol. 26, Issue 1
  • DOI: 10.1107/s1600577518015035

Fibril structure of amyloid-β(1–42) by cryo–electron microscopy
journal, September 2017


Imaging of neuronal tissues by x-ray diffraction and x-ray fluorescence microscopy: evaluation of contrast and biomarkers for neurodegenerative diseases
journal, January 2017

  • Carboni, Eleonora; Nicolas, Jan-David; Töpperwien, Mareike
  • Biomedical Optics Express, Vol. 8, Issue 10
  • DOI: 10.1364/boe.8.004331

X-ray diffraction reveals blunt-force loading threshold for nanoscopic structural change in ex vivo neuronal tissues
text, January 2019


Super‐Resolution Infrared Imaging of Polymorphic Amyloid Aggregates Directly in Neurons
journal, March 2020

  • Klementieva, Oxana; Sandt, Christophe; Martinsson, Isak
  • Advanced Science, Vol. 7, Issue 6
  • DOI: 10.1002/advs.201903004

Mining Disaggregase Sequence Space to Safely Counter TDP-43, FUS, and α-Synuclein Proteotoxicity
journal, August 2019


Structure of amyloid β25–35 in lipid environment and cholesterol-dependent membrane pore formation
journal, February 2019


Nanoscale structure of amyloid-β plaques in Alzheimer’s disease
journal, March 2019

  • Querol-Vilaseca, Marta; Colom-Cadena, Martí; Pegueroles, Jordi
  • Scientific Reports, Vol. 9, Issue 1
  • DOI: 10.1038/s41598-019-41443-3

Bacillus subtilis HelD, an RNA Polymerase Interacting Helicase, Forms Amyloid-Like Fibrils
journal, August 2018