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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

Controlled and Selective Photo-oxidation of Amyloid-β Fibrils by Oligomeric p-Phenylene Ethynylenes

Photodynamic therapy (PDT) has been explored as a therapeutic strategy to clear toxic amyloid aggregates involved in neurodegenerative disorders such as Alzheimer’s disease. A major limitation of PDT is off-target oxidation, which can be lethal for the surrounding cells. In this work, we have shown that a novel class of oligo-p-phenylene ethynylenes (OPEs) exhibit selective binding and fluorescence turn-on in the presence of prefibrillar and fibrillar aggregates of disease-relevant proteins such as amyloid-β (Aβ) and α-synuclein. Concomitant with fluorescence turn-on, OPE also photosensitizes singlet oxygen under illumination through the generation of a triplet state, pointing to the potential application of OPEs as photosensitizers in PDT. Herein, we investigated the photosensitizing activity of an anionic OPE for the photo-oxidation of Aβ fibrils and compared its efficacy to the well-known but nonselective photosensitizer methylene blue (MB). Our results show that, while MB photo-oxidized both monomeric and fibrillar conformers of Aβ40, OPE oxidized only Aβ40 fibrils, targeting two histidine residues on the fibril surface and a methionine residue located in the fibril core. Oxidized fibrils were shorter and more dispersed but retained the characteristic β-sheet rich fibrillar structure and the ability to seed further fibril growth. Importantly, the oxidized fibrils displayed low toxicity. We have thus discovered a class of novel theranostics for the simultaneous detection and oxidization of amyloid aggregates. Importantly, the selectivity of OPE’s photosensitizing activity overcomes the limitation of off-target oxidation of traditional photosensitizers and represents an advancement of PDT as a viable strategy to treat neurodegenerative disorders.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Amyloid-like amelogenin nanoribbons template mineralization via a low-energy interface of ion binding sites

Protein scaffolds direct the organization of amorphous precursors that transform into mineralized tissues, but the templating mechanism remains elusive. Motivated by models for the biomineralization of tooth enamel, wherein amyloid-like amelogenin nanoribbons guide the mineralization of apatite filaments, we investigated the impact of nanoribbon structure, sequence, and chemistry on amorphous calcium phosphate (ACP) nucleation. Using full-length human amelogenin and peptide analogs with an amyloid-like domain, films of β-sheet nanoribbons were self-assembled on graphite and characterized by in situ atomic force microscopy and molecular dynamics simulations. All sequences substantially reduce nucleation barriers for ACP by creating low-energy interfaces, while phosphoserines along the length of the nanoribbons dramatically enhance kinetic factors associated with ion binding. Furthermore, the distribution of negatively charged residues along the nanoribbons presents a potential match to the Ca–Ca distances of the multi-ion complexes that constitute ACP. These findings show that amyloid-like amelogenin nanoribbons provide potent scaffolds for ACP mineralization by presenting energetically and stereochemically favorable templates of calcium phosphate ion binding and suggest enhanced surface wetting toward calcium phosphates in general.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Structural mechanism for modulation of functional amyloid and biofilm formation by Staphylococcal Bap protein switch

The Staphylococcal Bap proteins sense environmental signals (such as pH, [Ca 2+ ]) to build amyloid scaffold biofilm matrices via unknown mechanisms. We here report the crystal structure of the aggregation-prone region of Staphylococcus aureus Bap which adopts a dumbbell-shaped fold. The middle module (MM) connecting the N-terminal and C-terminal lobes consists of a tandem of novel double-Ca 2+ -binding motifs involved in cooperative interaction networks, which undergoes Ca 2+ -dependent order-disorder conformational switches. The N-terminal lobe is sufficient to mediate amyloid aggregation through liquid-liquid phase separation and maturation, and subsequent biofilm formation under acidic conditions. Such processes are promoted by disordered MM at low [Ca 2+ ] but inhibited by ordered MM stabilized by Ca 2+ binding, with inhibition efficiency depending on structural integrity of the interaction networks. Furthermore, these studies illustrate a novel protein switch in pathogenic bacteria and provide insights into the mechanistic understanding of Bap proteins in modulation of functional amyloid and biofilm formation, which could be implemented in the anti-biofilm drug design.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

CryoEM structure of the low-complexity domain of hnRNPA2 and its conversion to pathogenic amyloid

hnRNPA2 is a human ribonucleoprotein (RNP) involved in RNA metabolism. It forms fibrils both under cellular stress and in mutated form in neurodegenerative conditions. Previous work established that the C-terminal low-complexity domain (LCD) of hnRNPA2 fibrillizes under stress, and missense mutations in this domain are found in the disease multisystem proteinopathy (MSP). However, little is known at the atomic level about the hnRNPA2 LCD structure that is involved in those processes and how disease mutations cause structural change. Here we present the cryo-electron microscopy (cryoEM) structure of the hnRNPA2 LCD fibril core and demonstrate its capability to form a reversible hydrogel in vitro containing amyloid-like fibrils. Whereas these fibrils, like pathogenic amyloid, are formed from protein chains stacked into β-sheets by backbone hydrogen bonds, they display distinct structural differences: the chains are kinked, enabling non-covalent cross-linking of fibrils and disfavoring formation of pathogenic steric zippers. Both reversibility and energetic calculations suggest these fibrils are less stable than pathogenic amyloid. Moreover, the crystal structure of the disease-mutation-containing segment (D290V) of hnRNPA2 suggests that the replacement fundamentally alters the fibril structure to a more stable energetic state. These findings illuminate how molecular interactions promote protein fibril networks and how mutation can transform fibril structure from functional to a pathogenic form.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Low complexity domains of the nucleocapsid protein of SARS-CoV-2 form amyloid fibrils

The self-assembly of the Nucleocapsid protein (NCAP) of SARS-CoV-2 is crucial for its function. Computational analysis of the amino acid sequence of NCAP reveals low-complexity domains (LCDs) akin to LCDs in other proteins known to self-assemble as phase separation droplets and amyloid fibrils. Previous reports have described NCAP’s propensity to phase-separate. Here we show that the central LCD of NCAP is capable of both, phase separation and amyloid formation. Within this central LCD we identified three adhesive segments and determined the atomic structure of the fibrils formed by each. Those structures guided the design of G12, a peptide that interferes with the self-assembly of NCAP and demonstrates antiviral activity in SARS-CoV-2 infected cells. Our work, therefore, demonstrates the amyloid form of the central LCD of NCAP and suggests that amyloidogenic segments of NCAP could be targeted for drug development.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Competition between inside-out unfolding and pathogenic aggregation in an amyloid-forming β-propeller

Studies of folded-to-misfolded transitions using model protein systems reveal a range of unfolding needed for exposure of amyloid-prone regions for subsequent fibrillization. Here, we probe the relationship between unfolding and aggregation for glaucoma-associated myocilin. Mutations within the olfactomedin domain of myocilin (OLF) cause a gain-of-function, namely cytotoxic intracellular aggregation, which hastens disease progression. Aggregation by wild-type OLF (OLF WT ) competes with its chemical unfolding, but only below the threshold where OLF loses tertiary structure. Representative moderate (OLF D380A ) and severe (OLF I499F ) disease variants aggregate differently, with rates comparable to OLF WT in initial stages of unfolding, and variants adopt distinct partially folded structures seen along the OLF WT urea-unfolding pathway. Whether initiated with mutation or chemical perturbation, unfolding propagates outward to the propeller surface. In sum, for this large protein prone to amyloid formation, the requirement for a conformational change to promote amyloid fibrillization leads to direct competition between unfolding and aggregation.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Label-free X-ray estimation of brain amyloid burden

Amyloid plaque deposits in the brain are indicative of Alzheimer’s and other diseases. Measurements of brain amyloid burden in small animals require laborious post-mortem histological analysis or resource-intensive, contrast-enhanced imaging techniques. We describe a label-free method based on spectral small-angle X-ray scattering with a polychromatic beam for in vivo estimation of brain amyloid burden. Our findings comparing 5XFAD versus wild-type mice correlate well with histology, showing promise for a fast and practical in vivo technique.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Phenol-soluble modulins PSMα3 and PSMβ2 form nanotubes that are cross-α amyloids

The formation of cross-α amyloids has been shown by crystallographic analysis of the highly cytolytic peptide PSMα3, a secreted virulence factor associated with the human pathogen Staphylococcus aureus . However, the relationship of the crystallographic cross-α structure to self-assembled filaments of PSMα3 and its relevance to other phenol-soluble modulin (PSM) peptides remained an open question. We report the cryo–electron microscopy structural analysis of three nanotubes derived from self-assembly of PSMα3 and PSMβ2 peptides in aqueous solution. In each case, the nanotubes are derived from self-association of cross-α amyloid protofilaments. The self-assembly behavior of S. aureus PSMα3 and PSMβ2 peptides provides strong evidence for the importance of the cross-α fold in self-assembled peptide and protein structures in general and for PSMs in particular.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Age, vascular disease, and Alzheimer’s disease pathologies in amyloid negative elderly adults

Background: We recently reported that CSF phosphorylated tau (p-Tau 181 ) relative to Aβ 40 (CSF p-Tau/Aβ 40 ratio) was less noisy and increased associations with Alzheimer’s disease (AD) biomarkers compared to CSF p-Tau 181 alone. While elevations of CSF p-Tau/Aβ 40 can occur in amyloid-β (Aβ) negative (Aβ-) individuals, the factors associated with these elevations and their role in neurodegeneration and cognitive decline are unknown. We aim to explore factors associated with elevated tau in CSF, and how these elevated tau are related to neurodegeneration and cognitive decline in the absence of Aβ positivity. Methods: We examined relationships between CSF p-Tau/Aβ 40 , and CSF Aβ 42 /Aβ 40 , Aβ PET, and white matter hyperintensities (WMH) as well as vascular risk factors in 149 cognitively unimpaired and 52 impaired individuals who were presumably not on the Alzheimer’s disease (AD) pathway due to negative Aβ status on both CSF and PET. Subgroups had 18 F-fluorodeoxyglucose (FDG) PET and adjusted hippocampal volume (aHCV), and longitudinal measures of CSF, aHCV, FDG PET, and cognition data, so we examined CSF p-Tau/Aβ 40 associations with these measures as well. Results: Elevated CSF p-Tau/Aβ 40 was associated with older age, male sex, greater WMH, and hypertension as well as a pattern of hippocampal atrophy and temporoparietal hypometabolism characteristic of AD. Lower CSF Aβ 42 /Aβ 40 , higher WMH, and hypertension but not age, sex, Aβ PET, APOE-ε4 status, body mass index, smoking, and hyperlipidemia at baseline predicted CSF p-Tau/Aβ 40 increases over approximately 5 years of follow-up. The relationship between CSF p-Tau/Aβ 40 and subsequent cognitive decline was partially or fully explained by neurodegenerative measurements. Conclusions: These data provide surprising clues as to the etiology and significance of tau pathology in the absence of Aβ. It seems likely that, in addition to age, both cerebrovascular disease and subthreshold levels of Aβ are related to this tau accumulation. Crucially, this phenotype of CSF tau elevation in amyloid-negative individuals share features with AD such as a pattern of metabolic decline and regional brain atrophy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Neurons die with heightened but functional macro- and chaperone mediated autophagy upon increased amyloid-ß induced toxicity with region-specific protection in prolonged intermittent fasting

Highlights: • Macroautophagy (MA) is strongly engaged upon APP overexpression and remains high over time. • APP colocalization with macroautophagy components remains increased until late, promoting continuous recruitment to the autophagy machinery. • Robust chaperone-mediated autophagy (CMA) engagement is observed in late APP overexpression. • Macroautophagic flux during APP overexpression is preserved, even at late time points, suggesting functional autophagy in the face of apoptosis onset. • Macroautophagy impairment increases markers of amyloidogenesis and further exacerbates the onset of apoptotic cell death. Alzheimer's disease (AD) is a devastating neurodegenerative condition with significant socio-economic impact that is exacerbated by the rapid increase in population aging, particularly impacting already burdened health care systems of poorly resourced countries. Accumulation of the amyloid-β (Aβ) peptide, generated through amyloid precursor protein (APP) processing, manifesting in senile plaques, is a well-established neuropathological feature. Aβ plays a key role in driving synaptic dysfunction, neuronal cell loss, glial cell activation and oxidative stress associated with the pathogenesis of AD. Thus, the enhanced clearance of Aβ peptide though modulation of the mechanisms that regulate intracellular Aβ metabolism and clearance during AD progression have received major attention. Autophagy, a lysosome-based major proteolytic pathway, plays a crucial role in intracellular protein quality control and has been shown to contribute to the clearance of Aβ peptide. However, to what extent autophagy activity remains upregulated and functional in the process of increasing Aβ neurotoxicity is largely unclear. Here, we investigated the extent of neuronal toxicity in vitro by characterising autophagic flux, the expression profile of key amyloidogenic proteins, and proteins associated with prominent subtypes of the autophagy pathway to dissect the interplay between the engagement of proteolytic pathways and cell death onset in the context of APP overexpression. Moreover, we assessed the neuroprotective effects of a caloric restriction regime in vivo on the modulation of autophagy in specific brain regions. Our results reveal that autophagy is upregulated in the presence of high levels of APP and Aβ and remains heightened and functional despite concomitant apoptosis induction, suggestive of a mismatch between autophagy cargo generation and clearance capacity. These findings were confirmed when implementing a prolonged intermittent fasting (IF) intervention in a model of paraquat-induced neuronal toxicity, where markers of autophagic activity were increased, while apoptosis onset and lipid peroxidation were robustly decreased in brain regions associated with neurodegeneration. This work highlights that especially caloric restriction mimetics and controlled prolonged IF may indeed be a highly promising therapeutic strategy at all stages of AD-associated pathology progression, for a cell-inherent and cell specific augmentation of Aβ clearance through the powerful engagement of autophagy and thereby robustly contributing to neuronal protection.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Antibodies Raised Against an Aβ Oligomer Mimic Recognize Pathological Features in Alzheimer’s Disease and Associated Amyloid-Disease Brain Tissue

Antibodies that target the β-amyloid peptide (Aβ) and its associated assemblies are important tools in Alzheimer’s disease research and have emerged as promising Alzheimer’s disease therapies. This paper reports the creation and characterization of a triangular Aβ trimer mimic composed of Aβ 17–36 β-hairpins and the generation and study of polyclonal antibodies raised against the Aβ trimer mimic. The Aβ trimer mimic is covalently stabilized by three disulfide bonds at the corners of the triangular trimer to create a homogeneous oligomer. Structural, biophysical, and cell-based studies demonstrate that the Aβ trimer mimic shares characteristics with oligomers of full-length Aβ. X-ray crystallography elucidates the structure of the trimer and reveals that four copies of the trimer assemble to form a dodecamer. SDS-PAGE, size exclusion chromatography, and dynamic light scattering reveal that the trimer also forms higher-order assemblies in solution. Cell-based toxicity assays show that the trimer elicits LDH release, decreases ATP levels, and activates caspase-3/7 mediated apoptosis. Immunostaining studies on brain slices from people who lived with Alzheimer’s disease and people who lived with Down syndrome reveal that the polyclonal antibodies raised against the Aβ trimer mimic recognize pathological features including different types of Aβ plaques and cerebral amyloid angiopathy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Surfactant-like peptide gels are based on cross-β amyloid fibrils

Surfactant-like peptides, in which hydrophilic and hydrophobic residues are encoded within different domains in the peptide sequence, undergo facile self-assembly in aqueous solution to form supramolecular hydrogels. These peptides have been explored extensively as substrates for the creation of functional materials since a wide variety of amphipathic sequences can be prepared from commonly available amino acid precursors. The self-assembly behavior of surfactant-like peptides has been compared to that observed for small molecule amphiphiles in which nanoscale phase separation of the hydrophobic domains drives the self-assembly of supramolecular structures. Here, we investigate the relationship between sequence and supramolecular structure for a pair of bola-amphiphilic peptides, Ac-KLIIIK-NH 2 (L2) and Ac-KIIILK-NH 2 (L5). Despite similar length, composition, and polar sequence pattern, L2 and L5 form morphologically distinct assemblies, nanosheets and nanotubes, respectively. Cryo-EM helical reconstruction was employed to determine the structure of the L5 nanotube at near-atomic resolution. Rather than displaying self-assembly behavior analogous to conventional amphiphiles, the packing arrangement of peptides in the L5 nanotube displayed steric zipper interfaces that resembled those observed in the structures of β-amyloid fibrils. Like amyloids, the supramolecular structures of the L2 and L5 assemblies were sensitive to conservative amino acid substitutions within an otherwise identical amphipathic sequence pattern. This study highlights the need to better understand the relationship between sequence and supramolecular structure to facilitate the development of functional peptide-based materials for biomaterials applications.

Das, Abhinaba [Emory University, Atlanta, GA (Unit↗
DOE OSTI2024

Tau accumulation and atrophy predict amyloid independent cognitive decline in aging

INTRODUCTION: Amyloid beta (Aβ) and tau pathology are cross-sectionally associated with atrophy and cognitive decline in aging and Alzheimer's disease (AD). METHODS: We investigated relationships between concurrent longitudinal measures of Aβ (Pittsburgh compound B [PiB] positron emission tomography [PET]), tau (flortaucipir [FTP] PET), atrophy (structural magnetic resonance imaging), episodic memory (EM), and non-memory (NM) in 78 cognitively healthy older adults (OA). RESULTS: Entorhinal FTP change was correlated with EM decline regardless of Aβ, but meta-temporal FTP and global PiB change were only associated with EM and NM decline in Aβ+ OA. Voxel-wise analyses revealed significant associations between temporal lobe FTP change and EM decline in all groups. PiB and FTP change were not associated with structural change, suggesting a functional or microstructural mechanism linking these measures to cognitive decline. DISCUSSION: Our results show that longitudinal Aβ is linked to cognitive decline only in the presence of elevated Aβ, but longitudinal temporal lobe tau is associated with memory decline regardless of Aβ status.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Impact of simulated reduced injected dose on the assessment of amyloid PET scans

To investigate the impact of reduced injected doses on the quantitative and qualitative assessment of the amyloid PET tracers [ 18 F]flutemetamol and [ 18 F]florbetaben. Cognitively impaired and unimpaired individuals (N = 250, 36% Aβ-positive) were included and injected with [ 18 F]flutemetamol (N = 175) or [ 18 F]florbetaben (N = 75). PET scans were acquired in list-mode (90–110 min post-injection) and reduced-dose images were simulated to generate images of 75, 50, 25, 12.5 and 5% of the original injected dose. Images were reconstructed using vendor-provided reconstruction tools and visually assessed for Aβ-pathology. SUVRs were calculated for a global cortical and three smaller regions using a cerebellar cortex reference tissue, and Centiloid was computed. Absolute and percentage differences in SUVR and CL were calculated between dose levels, and the ability to discriminate between Aβ- and Aβ + scans was evaluated using ROC analyses. Finally, intra-reader agreement between the reduced dose and 100% images was evaluated. At 5% injected dose, change in SUVR was 3.72% and 3.12%, with absolute change in Centiloid 3.35CL and 4.62CL, for [ 18 F]flutemetamol and [ 18 F]florbetaben, respectively. At 12.5% injected dose, percentage change in SUVR and absolute change in Centiloid were < 1.5%. AUCs for discriminating Aβ- from Aβ + scans were high (AUC ≥ 0.94) across dose levels, and visual assessment showed intra-reader agreement of > 80% for both tracers. This proof-of-concept study showed that for both [ 18 F]flutemetamol and [ 18 F]florbetaben, adequate quantitative and qualitative assessments can be obtained at 12.5% of the original injected dose. However, decisions to reduce the injected dose should be made considering the specific clinical or research circumstances.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2022

Design and synthesis of astatinated benzothiazole compounds for their potential use in Targeted Alpha Therapy (TAT) strategies to treat Alzheimer's disease-associated amyloid plaques

Alzheimer's disease (AD) is a terminal neurodegenerative disease characterized by the buildup of amyloid fibrils, amorphous aggregates and tauopathies. Several treatment modalities, which rely on various biological processes to reduce disease burden, have been largely ineffective at treating Alzheimer's disease. Targeted alpha therapy (TAT) has demonstrated positive results in the treatment of cancer. Benzothiazole derivatives have been successfully shown to target these plaques and are used in several imaging applications. One such derivative, Flutemetamol (Vizamyl TM ) is an FDA approved diagnostic tool for PET imaging of AD-associated plaques. We report the radiolabeling of benzothiazole derivatives with 211 At, a 7.2 h alpha emitting radionuclide, using a copper catalyzed reaction with a boronic acid precursor molecule. In conclusion, our final compound [ 211 At]3'-At-PIB-OMe had a radiochemical yield of 55% and was found to be stable for at least 3 h in phosphate buffered saline.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2020

Distinct effects of beta-amyloid and tau on cortical thickness in cognitively healthy older adults

Published reports of associations between β-amyloid (Aβ) and cortical integrity conflict. Tau biomarkers may help elucidate the complex relationship between pathology and neurodegeneration in aging. We measured cortical thickness using magnetic resonance imaging, Aβ using Pittsburgh compound B positron emission tomography (PiB-PET), and tau using flortaucipir (FTP)-PET in 125 cognitively normal older adults. We examined relationships among PET measures, cortical thickness, and cognition. Cortical thickness was reduced in PiB+/FTP+ participants compared to the PiB+/FTP– and PiB–/FTP– groups. Continuous PiB associations with cortical thickness were weak but positive in FTP– participants and negative in FTP+. FTP strongly negatively predicted thickness regardless of PiB status. FTP was associated with memory and cortical thickness, and mediated the association of PiB with memory. Past findings linking Aβ and cortical thickness are likely weak due to opposing effects of Aβ on cortical thickness relative to tau burden. Tau, in contrast to Aβ, is strongly related to cortical thickness and memory.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Positron emission tomography harmonization in the Alzheimer's Disease Neuroimaging Initiative: A scalable and rigorous approach to multisite amyloid and tau quantification

Abstract INTRODUCTION A key goal of the Alzheimer's Disease NeuroImaging Initiative (ADNI) positron emission tomography (PET) Core is to harmonize quantification of β‐amyloid (Aβ) and tau PET image data across multiple scanners and tracers. METHODS We developed an analysis pipeline (Berkeley PET Imaging Pipeline, B‐PIP) for ADNI Aβ and tau PET images and applied it to PET data from other multisite studies. Steps include image pre‐processing, refacing, magnetic resonance imaging (MRI)/PET co‐registration, visual quality control (QC), quantification of tracer uptake, and standardization of Aβ and tau standardized uptake value ratios (SUVrs) across tracers. RESULTS Measurements from 10,105 cross‐sectional and longitudinal Aβ and tau PET scans acquired in several studies between 2010 and 2024 can be processed, harmonized, and directly merged across tracers and cohorts. DISCUSSION The B‐PIP developed in ADNI is a scalable image harmonization approach used in several observational studies and clinical trials that facilitates rigorous Aβ and tau PET quantification and data sharing. Highlights Quantitative results from ADNI Aβ and tau PET data are generated using a rigorous, scalable image processing pipeline This pipeline has been applied to PET data from several other large, multisite studies and trials Quantitative outcomes are harmonizable across studies and are shared with the scientific community

Neurosciences & Neurology↗
DOE OSTI2021

Comparative Hydrophobic Core Dynamics Between Wild‐Type Amyloid‐β Fibrils, Glutamate‐3 Truncation, and Serine‐8 Phosphorylation

Abstract Post‐translational modifications (PTMs) of amyloid‐β (Aβ) species are implicated in the modulation of overall toxicities and aggregation propensities. We investigated the internal dynamics in the hydrophobic core of the truncated ΔE3 mutant fibrils of Aβ 1–40 and compared them with prior and new data for wild‐type fibrils as well as with phosphorylated S8 fibrils. Deuteron static solid‐state NMR techniques, spanning line‐shape analysis, longitudinal relaxation, and chemical exchange saturation transfer methods, were employed to assess the rotameric jumps of several methyl‐bearing and aromatic groups in the core of the fibrils. Taken together, the results indicate the rather significant influence of the PTMs on the hydrophobic core dynamics, which propagates far beyond the local site of the chemical modification. The phosphorylated S8 fibrils display an overall rigidifying of the core based on the higher activation barriers of motions than the wild‐type fibrils, whereas the ΔE3 fibrils induce a broader variety of changes, some of which are thermodynamic in nature rather than the kinetic ones.

Vugmeyster, Liliya↗