Conformational Basis for Asymmetric Seeding Barrier in Filaments of Three- and Four-Repeat Tau

Siddiqua, Ayisha; Luo, Yin; Meyer, Virginia; Swanson, Michael A.; Yu, Xiaoyan; Wei, Guanghong; Zheng, Jie; Eaton, Gareth R.; Ma, Buyong; Nussinov, Ruth; Eaton, Sandra S.; Margittai, Martin

doi:10.1021/ja303498q

Cited by 65 publications

(90 citation statements)

References 62 publications

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“…The locations of the HXPGGG motifs in the K18 monomer[58] (A) and K18 fibril[36, 59] (B). C. A model of full-length tau fibril structure[60].…”

Section: Figurementioning

confidence: 99%

“…DC8E8 is able to discriminate between the healthy and diseased tau proteome, making its epitopes suitable targets, and DC8E8 a suitable candidate molecule, for AD immunotherapy. [57] Figure 3 shows the location of the four motifs in K18 monomer[58] and K18 fibril[36, 59]. With the addition of the C- and N-terminal residues, the PGGG motifs could be buried inside.…”

Section: Introductionmentioning

confidence: 99%

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Conformational selection in amyloid-based immunotherapy: Survey of crystal structures of antibody-amyloid complexes

Zhao

Nussinov

2016

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background The dominant feature in neurodegenerative diseases is protein aggregations that lead to neuronal loss. Immunotherapies using antibodies or antibody fragments to target the aggregations are a highly perused approach. The molecular mechanisms underlying the amyloid-based immunotherapy are complex. Deciphering the properties of amyloidogenic proteins responsible for these diseases is essential to obtain insights into antibody recognition of the amyloid antigens. Scope of Review We systematically explore all available crystal structures of antibody-amyloid complexes related to neurodegenerative diseases, including antibodies that recognize the Aβ peptide, tau protein, prion protein, alpha-synuclein, huntingtin protein (mHTT), and polyglutamine. Major Conclusions We found that antibodies mostly use the conformational selection mechanism to recognize the highly flexible amyloid antigens. In particular, solanezumab bound to Aβ12–28 tripeptide motif conformation (F19F20A21), which is shared with the Aβ42 fibril. This motif, which is trapped by the antibody, may provide the missing link in amyloid formation. Water molecules often bridge between the antibody and amyloid, contributing to the recognition. General Significance This paper provides the structural basis for antibody recognition of amyloidogenic proteins. The analysis and discussion of known structures are expected to help in the design and optimization of antibodies in neurodegenerative diseases.

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“…The locations of the HXPGGG motifs in the K18 monomer[58] (A) and K18 fibril[36, 59] (B). C. A model of full-length tau fibril structure[60].…”

Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Conformational selection in amyloid-based immunotherapy: Survey of crystal structures of antibody-amyloid complexes

Zhao

Nussinov

2016

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…Both 3R- and 4R-tau are included in the NFTs of AD [36]. However, similar to Aβ, there may be isoform-specific characteristics in the aggregation and fibril-forming capacity of tau [37]. In general, with AD and other tauopathies, the dysregulation of tau phosphorylation and its subsequent aggregation into NFT structures impairs neuronal functioning and ultimately leads to cell death.…”

Section: Alzheimer’s Disease Pathologymentioning

confidence: 99%

Behavioral assays with mouse models of Alzheimer's disease: Practical considerations and guidelines

Puzzo

Lee

Palmeri

et al. 2014

Biochemical Pharmacology

168

120

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In Alzheimer’s disease (AD) basic research and drug discovery, mouse models are essential resources for uncovering biological mechanisms, validating molecular targets and screening potential compounds. Both transgenic and non-genetically modified mouse models enable access to different types of AD-like pathology in vivo. Although there is a wealth of genetic and biochemical studies on proposed AD pathogenic pathways, as a disease that centrally features cognitive failure, the ultimate readout for any interventions should be measures of learning and memory. This is particularly important given the lack of knowledge on disease etiology – assessment by cognitive assays offers the advantage of targeting relevant memory systems without requiring assumptions about pathogenesis. A multitude of behavioral assays are available for assessing cognitive functioning in mouse models, including ones specific for hippocampal-dependent learning and memory. Here we review the basics of available transgenic and non-transgenic AD mouse models and detail three well-established behavioral tasks commonly used for testing hippocampal-dependent cognition in mice – contextual fear conditioning, radial arm water maze and Morris water maze. In particular, we discuss the practical considerations, requirements and caveats of these behavioral testing paradigms.

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“…Both amyloid seeds from hIAPP and Aβ peptides could serve as the interacting precursors to mutually promote the amyloid elongation. Consistently, a number of studies have reported that amyloids from different species or with different sequences can overcome cross-seeding barriers to form cross-seeding aggregates and fibrils via the elongation pathway if they have close structural similarity, including tau-k18 and tau-k19 [84][85][86][87] , Aβ and tau 29 , and hIAPP and rIAPP 25 . Meanwhile, it is interesting to note that the tail-tail model also had a relatively higher population of 21.1%.…”

Section: Structural Populations Of Polymorphic Aβ-hiapp Assembliesmentioning

confidence: 80%

Polymorphic Associations and Structures of the Cross-Seeding of Aβ_1–42 and hIAPP_1–37 Polypeptides

Zhang¹,

Hu²,

Chen³

et al. 2015

J. Chem. Inf. Model.

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Emerging evidence have shown that the patients with Alzheimer's disease (AD) often have a higher risk of later developing type II diabetes (T2D), and vice versa, suggesting a potential pathological link between AD and T2D. Amyloid-β (Aβ) and human islet amyloid polypeptide (hIAPP) are the principle causative components responsible for the pathologies of AD and T2D, respectively. The cross-sequence interactions between Aβ and hIAPP may provide a molecular basis for better understanding the potential link between AD and T2D. Herein, we systematically modeled and simulated the cross-sequence aggregation process, molecular interactions, and polymorphic structures of full-length Aβ and hIAPP peptides using a combination of coarse-grained (CG) replica-exchange molecular dynamics (REMD) and all-atom molecular dynamics (MD) simulations, with particular focus on the effect of association models between Aβ and hIAPP on the structural stability and polymorphic populations of hybrid Aβ-hIAPP aggregates. Four distinct association models (double-layer, elongation, tail-tail, and block models) between Aβ and hIAPP oligomers were identified, and the associated polymorphic Aβ-hIAPP structures were determined as well. Among them, different association models led to different Aβ-hIAPP aggregates, with large differences in structural morphologies and populations, interacting interfaces, and underlying association forces. The computational models support the cross-sequence interactions between Aβ and hIAPP pentamers, which would lead to the complex hybrid Aβ-hIAPP assemblies. This computational work may also provide a different point of view to a better understanding of a potential link between AD and T2D.

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Conformational Basis for Asymmetric Seeding Barrier in Filaments of Three- and Four-Repeat Tau

Cited by 65 publications

References 62 publications

Conformational selection in amyloid-based immunotherapy: Survey of crystal structures of antibody-amyloid complexes

Conformational selection in amyloid-based immunotherapy: Survey of crystal structures of antibody-amyloid complexes

Behavioral assays with mouse models of Alzheimer's disease: Practical considerations and guidelines

Polymorphic Associations and Structures of the Cross-Seeding of Aβ_1–42 and hIAPP_1–37 Polypeptides

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Conformational Basis for Asymmetric Seeding Barrier in Filaments of Three- and Four-Repeat Tau

Cited by 65 publications

References 62 publications

Conformational selection in amyloid-based immunotherapy: Survey of crystal structures of antibody-amyloid complexes

Conformational selection in amyloid-based immunotherapy: Survey of crystal structures of antibody-amyloid complexes

Behavioral assays with mouse models of Alzheimer's disease: Practical considerations and guidelines

Polymorphic Associations and Structures of the Cross-Seeding of Aβ1–42 and hIAPP1–37 Polypeptides

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Polymorphic Associations and Structures of the Cross-Seeding of Aβ_1–42 and hIAPP_1–37 Polypeptides