Structural heterogeneity and intersubject variability of Aβ in familial and sporadic Alzheimer’s disease

Condello, Carlo; Lemmin, Thomas; Stöhr, Jan; Nick, Mimi; Wu, Yibing; Maxwell, Alison; Watts, Joel C.; Christoffer, D.; Oehler, Abby; Keene, C. Dirk; Bird, Thomas D.; Duinen, Sjoerd G. van; Lannfelt, Lars; Ingelsson, Martin; Graff, Caroline; Giles, Kurt; DeGrado, William F.; Prusiner, Stanley B.

doi:10.1073/pnas.1714966115

Cited by 121 publications

(133 citation statements)

References 68 publications

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“…that a mixture of tau isoforms formed in the complex environment of the brain is monomorphic whereas a single tau isoform fibrillized under controlled conditions is polymorphic. For comparison, AD brain-derived Aβ40 fibrils show a predominant structure within each brain but can differ between different brains (16), between different clinical subtypes (17,18), and between vascular and parenchymal compartments of a given brain (19). This in vivo polymorphism is qualitatively consistent with the polymorphism of in vitro Aβ40 fibrils (20)(21)(22).…”

Section: Significancesupporting

confidence: 54%

In vitro 0N4R tau fibrils contain a monomorphic β-sheet core enclosed by dynamically heterogeneous fuzzy coat segments

Dregni

Mandala

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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212

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Misfolding of the microtubule-binding protein tau into filamentous aggregates is characteristic of many neurodegenerative diseases such as Alzheimer’s disease and progressive supranuclear palsy. Determining the structures and dynamics of these tau fibrils is important for designing inhibitors against tau aggregation. Tau fibrils obtained from patient brains have been found by cryo-electron microscopy to adopt disease-specific molecular conformations. However, in vitro heparin-fibrillized 2N4R tau, which contains all four microtubule-binding repeats (4R), was recently found to adopt polymorphic structures. Here we use solid-state NMR spectroscopy to investigate the global fold and dynamics of heparin-fibrillized 0N4R tau. A single set of 13C and 15N chemical shifts was observed for residues in the four repeats, indicating a single β-sheet conformation for the fibril core. This rigid core spans the R2 and R3 repeats and adopts a hairpin-like fold that has similarities to but also clear differences from any of the polymorphic 2N4R folds. Obtaining a homogeneous fibril sample required careful purification of the protein and removal of any proteolytic fragments. A variety of experiments and polarization transfer from water and mobile side chains indicate that 0N4R tau fibrils exhibit heterogeneous dynamics: Outside the rigid R2–R3 core, the R1 and R4 repeats are semirigid even though they exhibit β-strand character and the proline-rich domains undergo large-amplitude anisotropic motions, whereas the two termini are nearly isotropically flexible. These results have significant implications for the structure and dynamics of 4R tau fibrils in vivo.

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Section: Significancesupporting

confidence: 54%

In vitro 0N4R tau fibrils contain a monomorphic β-sheet core enclosed by dynamically heterogeneous fuzzy coat segments

Dregni

Mandala

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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212

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“…An important indication that variant CJD (the human prionosis that is linked to bovine spongiform encephalopathy) is caused by a novel prion strain was the discovery of atypical lesions termed florid plaques in affected humans (Ironside et al, 2000). As in the case of PrP-prions, Aβ can fold into strain-like variants both in vitro (Petkova et al, 2005; Nilsson et al, 2007; Yagi et al, 2007; Paravastu et al, 2008; Meinhardt et al, 2009; Miller et al, 2010; Kodali et al, 2010; Agopian and Guo, 2012; Spirig et al, 2014; Tycko, 2015; Tycko, 2016) and in vivo (Meyer-Luehmann et al, 2006; Rosen et al, 2010; Rosen et al, 2011; Lu et al, 2013; Heilbronner et al, 2013; Watts et al, 2014; Stohr et al, 2014; Cohen et al, 2015; Condello et al, 2018; Rasmussen et al, 2017). Cerebral Aβ assemblies in humans with AD vary in terms of plaque morphology (Wisniewski et al, 1989; Thal et al, 2006), ligand binding characteristics (Rosen et al, 2010; Condello et al, 2018; Rasmussen et al, 2017), solid-state nuclear magnetic resonance features (Qiang et al, 2017), as well as conformational stability and other biophysical characteristics (Cohen et al, 2015).…”

Section: The Prion-like Properties Of Aggregated Aβmentioning

confidence: 99%

“…Cerebral Aβ assemblies in humans with AD vary in terms of plaque morphology (Wisniewski et al, 1989; Thal et al, 2006), ligand binding characteristics (Rosen et al, 2010; Condello et al, 2018; Rasmussen et al, 2017), solid-state nuclear magnetic resonance features (Qiang et al, 2017), as well as conformational stability and other biophysical characteristics (Cohen et al, 2015). Interestingly, Aβ extracted from the autopsied brains of nondemented elderly subjects exhibits molecular-level features that differ in some ways from AD-derived Aβ (Piccini et al, 2005; Portelius et al, 2015).…”

Section: The Prion-like Properties Of Aggregated Aβmentioning

confidence: 99%

Prion-like mechanisms in Alzheimer disease

Walker

2018

Handbook of Clinical Neurology

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Senile plaques and neurofibrillary tangles are the principal histopathologic hallmarks of Alzheimer disease. The essential constituents of these lesions are structurally abnormal variants of normally generated proteins: Aβ protein in plaques and tau protein in tangles. At the molecular level, both proteins in a pathogenic state share key properties with classic prions, i.e., they consist of alternatively folded, β-sheet-rich forms of the proteins that autopropagate by the seeded corruption and self-assembly of like proteins. Other similarities with prions include the ability to manifest as polymorphic and polyfunctional strains, resistance to chemical and enzymatic destruction, and the ability to spread within the brain and from the periphery to the brain. In Alzheimer disease, current evidence indicates that the pathogenic cascade follows from the endogenous, sequential corruption of Aβ and then tau. Therapeutic options include reducing the production or multimerization of the proteins, uncoupling the Aβ-tauopathy connection, or promoting the inactivation or removal of anomalous assemblies from the brain. Although aberrant Aβ appears to be the prime mover of Alzheimer disease pathogenesis, once set in motion by Aβ, the prion-like propagation of tauopathy may proceed independently of Aβ; if so, Aβ might be solely targeted as an early preventive measure, but optimal treatment of Alzheimer disease at later stages of the cascade could require intervention in both pathways.

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“…Furthermore, the phenomenon of amyloid polymorphism 62 might in part be related to the different nucleation mechanisms, where we hypothesize that the viral-catalyzed heterogeneously nucleated amyloids would be polymorphically distinct from homogeneouslynucleated amyloids that result from aberrant protein expression/overexpression. This hypothesis can be tested in future studies on the Aβ polymorphism in familial and sporadic Alzheimer's disease 63 , and whether this structural polymorphism can be traced back to different nucleation mechanisms related to different etiologies. Finally, the implication that viruses are capable of inducing conformational changes in bound host factors leading to exposure of cryptic epitopes may prove important for better understanding the correlation between viruses and autoimmune diseases.…”

Section: Discussionmentioning

confidence: 99%

The Viral Protein Corona Directs Viral Pathogenesis and Amyloid Aggregation

Ezzat

Pernemalm

Pålsson

et al. 2018

Preprint

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Nanoparticles accumulate a plethora of host factors on their surface (protein corona) in biological fluids, which influence the nanoparticle activity. Here we provide evidence for the existence of a rich viral protein corona and show its implications for viral infectivity, immune cell activation and catalysis of amyloid aggregation. We demonstrate that respiratory syncytial virus (RSV), a major cause of respiratory tract infections, accumulates a distinctive protein corona in different biofluids including: human plasma, human bronchoalveolar lavage fluid, non-human primate plasma and fetal bovine serum. Additionally, corona pre-coating differentially affects viral infectivity and its ability to activate human monocyte-derived dendritic cells (moDCs) depending on the biofluid.Furthermore, we demonstrate that cell-free RSV can bind and catalyze the amyloid aggregation of an amyloidogenic peptide derived from the islet amyloid polypeptide (IAPP) via surface-assisted nucleation.Similarly, we show that herpes simplex virus 1 (HSV-1) catalyzes the amyloid aggregation of the amyloid-beta (Aβ 42 ) peptide which is the major constituent of amyloid plaques in Alzheimer's disease. Our results provide a proof-of-concept for the presence of a viral protein corona layer that is dependent on the microenvironment and influences viral-host interactions. Additionally, the demonstration of viral nanosurface driven amyloid catalysis in an extracellular environment illustrates convergence between viral and amyloid pathologies suggesting a novel mechanistic link that warrants further investigation.

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Structural heterogeneity and intersubject variability of Aβ in familial and sporadic Alzheimer’s disease

Cited by 121 publications

References 68 publications

In vitro 0N4R tau fibrils contain a monomorphic β-sheet core enclosed by dynamically heterogeneous fuzzy coat segments

In vitro 0N4R tau fibrils contain a monomorphic β-sheet core enclosed by dynamically heterogeneous fuzzy coat segments

Prion-like mechanisms in Alzheimer disease

The Viral Protein Corona Directs Viral Pathogenesis and Amyloid Aggregation

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