Crystal structure of a conformational antibody that binds tau oligomers and inhibits pathological seeding by extracts from donors with Alzheimer's disease

Abskharon, Romany; Seidler, Paul M.; Sawaya, Michael R.; Cascio, Duilio; Yang, Tianxiao P.; Philipp, Stephan; Williams, Christopher Kazu; Newell, Kathy L.; Ghetti, Bernardino; DeTure, Michael A.; Dickson, Dennis W.; Vinters, Harry V.; Felgner, Philip L.; Nakajima, Rie; Glabe, Charles G.; Eisenberg, David S.

doi:10.1074/jbc.RA120.013638

Title: Crystal structure of a conformational antibody that binds tau oligomers and inhibits pathological seeding by extracts from donors with Alzheimer's disease

Journal Article · Wed Jul 01 00:00:00 EDT 2020 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.RA120.013638· OSTI ID:1769480

;

; Cascio, Duilio; Yang, Tianxiao P.; Philipp, Stephan; Williams, Christopher Kazu;

;

; Dickson, Dennis W.; Vinters, Harry V.;

; Nakajima, Rie; Glabe, Charles G.;

Soluble oligomers of aggregated tau accompany the accumulation of insoluble amyloid fibrils, a histological hallmark of Alzheimer disease (AD) and two dozen related neurodegenerative diseases. Both oligomers and fibrils seed the spread of Tau pathology, and by virtue of their low molecular weight and relative solubility, oligomers may be particularly pernicious seeds. Here, we report the formation of in vitro tau oligomers formed by an ionic liquid (IL15). Using IL15-induced recombinant tau oligomers and a dot blot assay, we discovered a mAb (M204) that binds oligomeric tau, but not tau monomers or fibrils. M204 and an engineered single-chain variable fragment (scFv) inhibited seeding by IL15-induced tau oligomers and pathological extracts from donors with AD and chronic traumatic encephalopathy. This finding suggests that M204-scFv targets pathological structures that are formed by tau in neurodegenerative diseases. We found that M204-scFv itself partitions into oligomeric forms that inhibit seeding differently, and crystal structures of the M204-scFv monomer, dimer, and trimer revealed conformational differences that explain differences among these forms in binding and inhibition. The efficiency of M204-scFv antibodies to inhibit the seeding by brain tissue extracts from different donors with tauopathies varied among individuals, indicating the possible existence of distinct amyloid polymorphs. We propose that by binding to oligomers, which are hypothesized to be the earliest seeding-competent species, M204-scFv may have potential as an early-stage diagnostic for AD and tauopathies, and also could guide the development of promising therapeutic antibodies.

View Journal Article

Cite

Export

Save

Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH)

Contributing Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

OSTI ID:: 1769480

Alternate ID(s):: OSTI ID: 1669129

Journal Information:: Journal of Biological Chemistry, Journal Name: Journal of Biological Chemistry Vol. 295 Journal Issue: 31; ISSN 0021-9258

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

References (62)

Conformation dependent monoclonal antibodies distinguish different replicating strains or conformers of prefibrillar Aβ oligomers Kayed, Rakez; Canto, Isabel; Breydo, Leonid Molecular Neurodegeneration, Vol. 5, Issue 1 https://doi.org/10.1186/1750-1326-5-57	journal	January 2010
Binding Efficiency of Protein–Protein Complexes Day, Eric S.; Cote, Shaun M.; Whitty, Adrian Biochemistry, Vol. 51, Issue 45 https://doi.org/10.1021/bi301039t	journal	November 2012
Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Goedert, M.; Wischik, C. M.; Crowther, R. A. Proceedings of the National Academy of Sciences, Vol. 85, Issue 11 https://doi.org/10.1073/pnas.85.11.4051	journal	June 1988
Influence of molecular size on tissue distribution of antibody fragments Li, Zhe; Krippendorff, Ben-Fillippo; Sharma, Sharad mAbs, Vol. 8, Issue 1 https://doi.org/10.1080/19420862.2015.1111497	journal	October 2015
Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules Falcon, Benjamin; Zivanov, Jasenko; Zhang, Wenjuan Nature, Vol. 568, Issue 7752 https://doi.org/10.1038/s41586-019-1026-5	journal	March 2019
The Role of Tau Oligomers in the Onset of Alzheimer's Disease Neuropathology Cárdenas-Aguayo, María del Carmen; Gómez-Virgilio, Laura; DeRosa, Steven ACS Chemical Neuroscience, Vol. 5, Issue 12 https://doi.org/10.1021/cn500148z	journal	September 2014
Extracellular Tau Oligomers Produce An Immediate Impairment of LTP and Memory Fá, M.; Puzzo, D.; Piacentini, R. Scientific Reports, Vol. 6, Issue 1 https://doi.org/10.1038/srep19393	journal	January 2016
Engineering production of functional scFv antibody in E. coli by co-expressing the molecule chaperone Skp Wang, Rongzhi; Xiang, Shuangshuang; Feng, Youjun Frontiers in Cellular and Infection Microbiology, Vol. 3 https://doi.org/10.3389/fcimb.2013.00072	journal	January 2013
Internalized Tau Oligomers Cause Neurodegeneration by Inducing Accumulation of Pathogenic Tau in Human Neurons Derived from Induced Pluripotent Stem Cells Usenovic, M.; Niroomand, S.; Drolet, R. E. Journal of Neuroscience, Vol. 35, Issue 42 https://doi.org/10.1523/JNEUROSCI.1523-15.2015	journal	October 2015
Invited review: Frontotemporal dementia caused by microtubule-associated protein tau gene ( MAPT ) mutations: a chameleon for neuropathology and neuroimaging Ghetti, Bernardino; Oblak, Adrian L.; Boeve, Bradley F. Neuropathology and Applied Neurobiology, Vol. 41, Issue 1 https://doi.org/10.1111/nan.12213	journal	January 2015
Suppression and dissolution of amyloid aggregates using ionic liquids Takekiyo, Takahiro; Yoshimura, Yukihiro Biophysical Reviews, Vol. 10, Issue 3 https://doi.org/10.1007/s12551-018-0421-8	journal	April 2018
The widespread alteration of neurites in Alzheimer's disease may be unrelated to amyloid deposition Tabaton, Massimo; Mandybur, Thaddeus I.; Perry, George Annals of Neurology, Vol. 26, Issue 6 https://doi.org/10.1002/ana.410260614	journal	December 1989
Prion-like transmission of protein aggregates in neurodegenerative diseases Brundin, Patrik; Melki, Ronald; Kopito, Ron Nature Reviews Molecular Cell Biology, Vol. 11, Issue 4 https://doi.org/10.1038/nrm2873	journal	April 2010
Passive Immunization in JNPL3 Transgenic Mice Using an Array of Phospho-Tau Specific Antibodies d’Abramo, Cristina; Acker, Christopher M.; Jimenez, Heidy PLOS ONE, Vol. 10, Issue 8 https://doi.org/10.1371/journal.pone.0135774	journal	August 2015
Structure-based inhibitors of tau aggregation Seidler, P. M.; Boyer, D. R.; Rodriguez, J. A. Nature Chemistry, Vol. 10, Issue 2 https://doi.org/10.1038/nchem.2889	journal	November 2017
Single-chain antigen-binding proteins Bird, R.; Hardman, K.; Jacobson, J. Science, Vol. 242, Issue 4877 https://doi.org/10.1126/science.3140379	journal	October 1988
Tau seeding activity begins in the transentorhinal/entorhinal regions and anticipates phospho-tau pathology in Alzheimer’s disease and PART Kaufman, Sarah K.; Del Tredici, Kelly; Thomas, Talitha L. Acta Neuropathologica, Vol. 136, Issue 1 https://doi.org/10.1007/s00401-018-1855-6	journal	May 2018
Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis Kayed, R. Science, Vol. 300, Issue 5618 https://doi.org/10.1126/science.1079469	journal	April 2003
Alzheimer brain-derived tau oligomers propagate pathology from endogenous tau Lasagna-Reeves, Cristian A.; Castillo-Carranza, Diana L.; Sengupta, Urmi Scientific Reports, Vol. 2, Issue 1 https://doi.org/10.1038/srep00700	journal	October 2012
Common fibrillar spines of amyloid-β and human islet amyloid polypeptide revealed by microelectron diffraction and structure-based inhibitors Krotee, Pascal; Griner, Sarah L.; Sawaya, Michael R. Journal of Biological Chemistry, Vol. 293, Issue 8 https://doi.org/10.1074/jbc.M117.806109	journal	December 2017
Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice Lasagna-Reeves, Cristian A.; Castillo-Carranza, Diana L.; Sengupta, Urmi Molecular Neurodegeneration, Vol. 6, Issue 1 https://doi.org/10.1186/1750-1326-6-39	journal	January 2011
Disulfide Bond Introduction for General Stabilization of Immunoglobulin Heavy-Chain Variable Domains Saerens, Dirk; Conrath, Katja; Govaert, Jochen Journal of Molecular Biology, Vol. 377, Issue 2 https://doi.org/10.1016/j.jmb.2008.01.022	journal	March 2008
The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics Hardy, J. Science, Vol. 297, Issue 5580 https://doi.org/10.1126/science.1072994	journal	July 2002
Development trends for therapeutic antibody fragments Nelson, Aaron L.; Reichert, Janice M. Nature Biotechnology, Vol. 27, Issue 4 https://doi.org/10.1038/nbt0409-331	journal	April 2009
Diversity in the CDR3 Region of VH Is Sufficient for Most Antibody Specificities Xu, John L.; Davis, Mark M. Immunity, Vol. 13, Issue 1 https://doi.org/10.1016/S1074-7613(00)00006-6	journal	July 2000
The Alzheimer-like phosphorylation of tau protein reduces microtubule binding and involves Ser-Pro and Thr-Pro motifs Gustke, N.; Steiner, B.; Mandelkow, E. -M. FEBS Letters, Vol. 307, Issue 2 https://doi.org/10.1016/0014-5793(92)80767-B	journal	July 1992
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
NIH Image to ImageJ: 25 years of image analysis Schneider, Caroline A.; Rasband, Wayne S.; Eliceiri, Kevin W. Nature Methods, Vol. 9, Issue 7 https://doi.org/10.1038/nmeth.2089	journal	June 2012
Enzymatic assembly of DNA molecules up to several hundred kilobases Gibson, Daniel G.; Young, Lei; Chuang, Ray-Yuan Nature Methods, Vol. 6, Issue 5, p. 343-345 https://doi.org/10.1038/nmeth.1318	journal	April 2009
Specific chemical and structural damage to proteins produced by synchrotron radiation Weik, M.; Ravelli, R. B. G.; Kryger, G. Proceedings of the National Academy of Sciences, Vol. 97, Issue 2 https://doi.org/10.1073/pnas.97.2.623	journal	January 2000
Out-of-register -sheets suggest a pathway to toxic amyloid aggregates Liu, C.; Zhao, M.; Jiang, L. Proceedings of the National Academy of Sciences, Vol. 109, Issue 51 https://doi.org/10.1073/pnas.1218792109	journal	December 2012
Characterization of Prefibrillar Tau Oligomers in Vitro and in Alzheimer Disease Patterson, Kristina R.; Remmers, Christine; Fu, Yifan Journal of Biological Chemistry, Vol. 286, Issue 26 https://doi.org/10.1074/jbc.M111.237974	journal	May 2011
Macrocyclic β-Sheet Peptides That Inhibit the Aggregation of a Tau-Protein-Derived Hexapeptide Zheng, Jing; Liu, Cong; Sawaya, Michael R. Journal of the American Chemical Society, Vol. 133, Issue 9 https://doi.org/10.1021/ja110545h	journal	March 2011
Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation Sievers, Stuart A.; Karanicolas, John; Chang, Howard W. Nature, Vol. 475, Issue 7354 https://doi.org/10.1038/nature10154	journal	June 2011
Toward a Unified Scheme for the Aggregation of Tau into Alzheimer Paired Helical Filaments ^† Barghorn, S.; Mandelkow, E. Biochemistry, Vol. 41, Issue 50 https://doi.org/10.1021/bi026469j	journal	December 2002
Human anti-self antibodies with high specificity from phage display libraries. Griffiths, A. D.; Malmqvist, M.; Marks, J. D. The EMBO Journal, Vol. 12, Issue 2 https://doi.org/10.1002/j.1460-2075.1993.tb05706.x	journal	February 1993
Structures of filaments from Pick’s disease reveal a novel tau protein fold Falcon, Benjamin; Zhang, Wenjuan; Murzin, Alexey G. Nature, Vol. 561, Issue 7721 https://doi.org/10.1038/s41586-018-0454-y	journal	August 2018
Passive Immunization with Tau Oligomer Monoclonal Antibody Reverses Tauopathy Phenotypes without Affecting Hyperphosphorylated Neurofibrillary Tangles Castillo-Carranza, D. L.; Sengupta, U.; Guerrero-Munoz, M. J. Journal of Neuroscience, Vol. 34, Issue 12 https://doi.org/10.1523/JNEUROSCI.3192-13.2014	journal	March 2014
Insights into the mechanism of X-ray-induced disulfide-bond cleavage in lysozyme crystals based on EPR, optical absorption and X-ray diffraction studies Sutton, Kristin A.; Black, Paul J.; Mercer, Kermit R. Acta Crystallographica Section D Biological Crystallography, Vol. 69, Issue 12 https://doi.org/10.1107/S0907444913022117	journal	November 2013
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
Ionic Liquid-Induced Formation of the α-Helical Structure of β-Lactoglobulin Takekiyo, Takahiro; Koyama, Yoshihiro; Yamazaki, Kumiko The Journal of Physical Chemistry B, Vol. 117, Issue 35 https://doi.org/10.1021/jp405834n	journal	August 2013
Soluble protein oligomers as emerging toxins in alzheimer's and other amyloid diseases Ferreira, Sergio T.; Vieira, Marcelo N. N.; De Felice, Fernanda G. IUBMB Life, Vol. 59, Issue 4 https://doi.org/10.1080/15216540701283882	journal	January 2007
Neuropathological Alterations in Alzheimer Disease Serrano-Pozo, A.; Frosch, M. P.; Masliah, E. Cold Spring Harbor Perspectives in Medicine, Vol. 1, Issue 1 https://doi.org/10.1101/cshperspect.a006189	journal	September 2011
Short Fibrils Constitute the Major Species of Seed-Competent Tau in the Brains of Mice Transgenic for Human P301S Tau Jackson, Samuel J.; Kerridge, Caroline; Cooper, Jane The Journal of Neuroscience, Vol. 36, Issue 3 https://doi.org/10.1523/JNEUROSCI.3542-15.2016	journal	January 2016
Atomic structures of amyloid cross-β spines reveal varied steric zippers Sawaya, Michael R.; Sambashivan, Shilpa; Nelson, Rebecca Nature, Vol. 447, Issue 7143 https://doi.org/10.1038/nature05695	journal	April 2007
Tau Prion Strains Dictate Patterns of Cell Pathology, Progression Rate, and Regional Vulnerability In Vivo Kaufman, Sarah K.; Sanders, David W.; Thomas, Talitha L. Neuron, Vol. 92, Issue 4 https://doi.org/10.1016/j.neuron.2016.09.055	journal	November 2016
Crystal structure of a conformation-dependent rabbit IgG Fab specific for amyloid prefibrillar oligomers Arai, Hiromi; Glabe, Charles; Luecke, Hartmut Biochimica et Biophysica Acta (BBA) - General Subjects, Vol. 1820, Issue 12 https://doi.org/10.1016/j.bbagen.2012.08.016	journal	December 2012
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Atomic structures of fibrillar segments of hIAPP suggest tightly mated β-sheets are important for cytotoxicity Krotee, Pascal; Rodriguez, Jose A.; Sawaya, Michael R. eLife, Vol. 6 https://doi.org/10.7554/eLife.19273	journal	January 2017
Tau in neurodegenerative disease Gao, Yong-Lei; Wang, Nan; Sun, Fu-Rong Annals of Translational Medicine, Vol. 6, Issue 10 https://doi.org/10.21037/atm.2018.04.23	journal	May 2018
Worldwide trends in the prevalence of dementia Cova, Ilaria; Markova, Anna; Campini, Isabella Journal of the Neurological Sciences, Vol. 379 https://doi.org/10.1016/j.jns.2017.06.030	journal	August 2017
Factors Influencing the Dimer to Monomer Transition of an Antibody Single-Chain Fv Fragment ^† Arndt, Katja M.; Müller, Kristian M.; Plückthun, Andreas Biochemistry, Vol. 37, Issue 37 https://doi.org/10.1021/bi9810407	journal	September 1998
Dementia From Alzheimer Disease and Mixed Pathologies in the Oldest Old James, Bryan D. JAMA, Vol. 307, Issue 17 https://doi.org/10.1001/jama.2012.3556	journal	May 2012
Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s disease Brier, Matthew R.; Gordon, Brian; Friedrichsen, Karl Science Translational Medicine, Vol. 8, Issue 338 https://doi.org/10.1126/scitranslmed.aaf2362	journal	May 2016
Preparation of stable tau oligomers for cellular and biochemical studies Karikari, Thomas K.; Nagel, David A.; Grainger, Alastair Analytical Biochemistry, Vol. 566 https://doi.org/10.1016/j.ab.2018.10.013	journal	February 2019
Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers Kayed, Rakez; Head, Elizabeth; Sarsoza, Floyd Molecular Neurodegeneration, Vol. 2, Issue 1 https://doi.org/10.1186/1750-1326-2-18	journal	January 2007
Monoclonal Antibodies against Aβ42 Fibrils Distinguish Multiple Aggregation State Polymorphisms in Vitro and in Alzheimer Disease Brain Hatami, Asa; Albay, Ricardo; Monjazeb, Sanaz Journal of Biological Chemistry, Vol. 289, Issue 46 https://doi.org/10.1074/jbc.M114.594846	journal	October 2014
Conformational Abs recognizing a generic amyloid fibril epitope O'Nuallain, B.; Wetzel, R. Proceedings of the National Academy of Sciences, Vol. 99, Issue 3 https://doi.org/10.1073/pnas.022662599	journal	January 2002
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Probing the N-Terminal β-Sheet Conversion in the Crystal Structure of the Human Prion Protein Bound to a Nanobody Abskharon, Romany N. N.; Giachin, Gabriele; Wohlkonig, Alexandre Journal of the American Chemical Society, Vol. 136, Issue 3 https://doi.org/10.1021/ja407527p	journal	January 2014
Identification of oligomers at early stages of tau aggregation in Alzheimer's disease Lasagna‐Reeves, Cristian A.; Castillo‐Carranza, Diana L.; Sengupta, Urmi The FASEB Journal, Vol. 26, Issue 5 https://doi.org/10.1096/fj.11-199851	journal	January 2012
Propagation of Tau Aggregates and Neurodegeneration Goedert, Michel; Eisenberg, David S.; Crowther, R. Anthony Annual Review of Neuroscience, Vol. 40, Issue 1 https://doi.org/10.1146/annurev-neuro-072116-031153	journal	July 2017

Similar Records

Alzheimer's-associated A{beta} oligomers show altered structure, immunoreactivity and synaptotoxicity with low doses of oleocanthal

Journal Article · Thu Oct 15 00:00:00 EDT 2009 · Toxicology and Applied Pharmacology · OSTI ID:1769480

Pitt, Jason; Roth, William; Lacor, Pascale; +5 more

Key residues for the oligomerization of A{beta}42 protein in Alzheimer's disease

Journal Article · Fri Oct 28 00:00:00 EDT 2011 · Biochemical and Biophysical Research Communications · OSTI ID:1769480

Ngo, Sam; Guo, Zhefeng

Three-repeat and four-repeat tau isoforms form different oligomers

Journal Article · Mon Dec 13 00:00:00 EST 2021 · Protein Science · OSTI ID:1769480

Shahpasand‐Kroner, Hedieh; Portillo, Jennifer; Lantz, Carter; +4 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
amyloid
tau
prion
inhibitor
fibril
protein structure
antibody
neurodegeneration
tauopathy
protein aggregation
neurodegenerative disease
oligomerization
Alzheimer disease
antibody engineering
protein crystallization

Title: Crystal structure of a conformational antibody that binds tau oligomers and inhibits pathological seeding by extracts from donors with Alzheimer's disease

Citation Formats

References (62)

Similar Records

Related Subjects