Search NASA⌕ Search

SEARCH · Search NASA

Results for “amyloids”

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.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Vascular endothelial growth factor receptor-1 (FLT1) interactions with amyloid-beta in Alzheimer’s disease: A putative biomarker of amyloid-induced vascular damage

We have identified FLT1 as a protein that changes during Alzheimer's disease (AD) whereby higher brain protein levels are associated with more amyloid, more tau, and faster longitudinal cognitive decline. Given FLT1's role in angiogenesis and immune activation, we hypothesized that FLT1 is upregulated in response to amyloid pathology, driving a vascular-immune cascade resulting in neurodegeneration and cognitive decline. We sought to determine (1) if in vivo FLT1 levels (CSF and plasma) associate with biomarkers of AD neuropathology or differ between diagnostic staging in an aged cohort enriched for early disease, and (2) whether FLT1 expression interacts with amyloid on downstream outcomes, such as phosphorylated tau levels and cognitive performance. Additionally, we sought to replicate FLT1 interactions in the brain. The results showed that higher levels of FLT1 in CSF and post-mortem brain tissue related to increased tau, particularly among amyloid positive individuals. These analyses help clarify the potential utility of FLT1 as a biomarker among individuals with evidence of brain amyloidosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Label-Free In Situ Chemical Characterization of Amyloid Plaques in Human Brain Tissues

The accumulation of amyloid plaques and increased brain redox burdens are neuropathological hallmarks of Alzheimer’s disease. Altered metabolism of essential biometals is another feature of Alzheimer’s, with amyloid plaques representing sites of disturbed metal homeostasis. Despite these observations, metal-targeting disease treatments have not been therapeutically effective to date. A better understanding of amyloid plaque composition and the role of the metals associated with them is critical. To establish this knowledge, the ability to resolve chemical variations at nanometer length scales relevant to biology is essential. Here, we present a methodology for the label-free, nanoscale chemical characterization of amyloid plaques within human Alzheimer’s disease tissue using synchrotron X-ray spectromicroscopy. Our approach exploits a C–H carbon absorption feature, consistent with the presence of lipids, to visualize amyloid plaques selectively against the tissue background, allowing chemical analysis to be performed without the addition of amyloid dyes that alter the native sample chemistry. Using this approach, we show that amyloid plaques contain elevated levels of calcium, carbonates, and iron compared to the surrounding brain tissue. Chemical analysis of iron within plaques revealed the presence of chemically reduced, low-oxidation-state phases, including ferromagnetic metallic iron. The zero-oxidation state of ferromagnetic iron determines its high chemical reactivity and so may contribute to the redox burden in the Alzheimer’s brain and thus drive neurodegeneration. Ferromagnetic metallic iron has no established physiological function in the brain and may represent a target for therapies designed to lower redox burdens in Alzheimer’s disease. Additionally, ferromagnetic metallic iron has magnetic properties that are distinct from the iron oxide forms predominant in tissue, which might be exploitable for the in vivo detection of amyloid pathologies using magnetically sensitive imaging. We anticipate that this label-free X-ray imaging approach will provide further insights into the chemical composition of amyloid plaques, facilitating better understanding of how plaques influence the course of Alzheimer’s disease.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
NASA NTRSDate not supplied

Understanding amyloids to prevent biofilm formation in space

There is a pressing need to search for novel approaches to combat biofilm formation, both in space and in medical applications. Many proteins have the ability to form ordered aggregates called amyloids. Amyloids are known to be an important part of biofilms. The use of anti-amyloid drugs is a novel venue for the development of antimicrobial agents. The ultrastructure of the amyloid aggregate shows a high packing of proteins, the second-order structure of which is dominated by β-sheets. The ability to form an amyloid aggregate is especially typical for proteins containing domains (protein fragments) with sufficient lability to arrange themselves in a tight β-sheet structure. Bioinformatics tools allow the prediction of such behavior of proteins in genomic data. We use GeneLab data of microbial populations identified aboard the International Space Station and other spacecraft to look for bacterial species that utilize amyloid aggregation in biofilm formation. We use a combined bioinformatic approach with a relatively high throughput molecular biology assay and biophysical assays to evaluate the anti-amyloid anti-biofilm approach. The significance of the research extends from understanding basic microbial community responses to spaceflight, to biofouling of the built environments in space as well as the long-term health of astronauts. Bioinformatics shows that onboard the ISS, bacterial species produce far more amyloid and prion proteins than are currently verified, hence their role in bacterial ecosystems is largely unknown. As we propose there is a link between amyloid formation in space and biofilm production, this research should lead to new paths for biofilm remediation in space.

Tomasz Zajkowski↗
DOE OSTI2022

De novo designed protein inhibitors of amyloid aggregation and seeding

Neurodegenerative diseases are characterized by the pathologic accumulation of aggregated proteins. Known as amyloid, these fibrillar aggregates include proteins such as tau and amyloid-β (Aβ) in Alzheimer’s disease (AD) and alpha-synuclein (αSyn) in Parkinson’s disease (PD). The development and spread of amyloid fibrils within the brain correlates with disease onset and progression, and inhibiting amyloid formation is a possible route toward therapeutic development. Recent advances have enabled the determination of amyloid fibril structures to atomic-level resolution, improving the possibility of structure-based inhibitor design. In this work, we use these amyloid structures to design inhibitors that bind to the ends of fibrils, “capping” them so as to prevent further growth. Using de novo protein design, we develop a library of miniprotein inhibitors of 35 to 48 residues that target the amyloid structures of tau, Aβ, and αSyn. Biophysical characterization of top in silico designed inhibitors shows they form stable folds, have no sequence similarity to naturally occurring proteins, and specifically prevent the aggregation of their targeted amyloid-prone proteins in vitro. The inhibitors also prevent the seeded aggregation and toxicity of fibrils in cells. In vivo evaluation reveals their ability to reduce aggregation and rescue motor deficits in Caenorhabditis elegans models of PD and AD.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Calibration of multisite raters for prospective visual reads of amyloid PET scans

Abstract INTRODUCTION In multicenter Alzheimer's disease studies, amyloid positron emission tomography (PET) visual reads are typically performed centrally by a few experts. Incorporating a broader reader network enhances scalability and generalizability. METHODS Ten neuroimaging experts from eight Alzheimer's Disease Research Centers (ADRCs) visually read 180 amyloid PET scans (30 scans and 15 duplicate scans for each of four tracers, imaged across a wide variety of scanners), using preferred reading software without anatomical imaging or quantitation. Scans were classified as elevated or non‐elevated per tracer‐specific criteria. Inter‐ and intra‐rater agreement was assessed. RESULTS Inter‐rater agreement was substantial (Fleiss’κ = 0.78), with full consensus on 69% of scans. Inter‐rater reliability was substantial to perfect across tracers (Fleiss’κ = 0.70–0.87). Intra‐rater agreement was substantial to perfect (Cohen'sκ = 0.79‐1). Scans with intermediate (10–40 Centiloid) quantitation had lower reader agreement. DISCUSSION A multicenter expert network achieved substantial agreement classifying amyloid PET scans. These scans provide a standard for reader training and reliability assurance in future studies. Highlights Calibration methods ensure reliable amyloid positron emission tomography (PET) visual reads across multiple raters. Substantial agreement is possible across readers using their preferred tools. Agreement is also substantial regardless of the amyloid PET tracer used. Scans with intermediate (10–40 Centiloid) quantitation have lower reader agreement. The calibration set will become a training tool for amyloid PET visual read studies.

Neurosciences & Neurology↗
DOE OSTI2022

Diabetes and hypertension are related to amyloid-beta burden in the population-based Rotterdam Study

Abstract Higher vascular disease burden increases the likelihood of developing dementia, including Alzheimer’s disease. Better understanding the association between vascular risk factors and Alzheimer’s disease pathology at the predementia stage is critical for developing effective strategies to delay cognitive decline. In this work, we estimated the impact of six vascular risk factors on the presence and severity of in vivo measured brain amyloid-beta (Aβ) plaques in participants from the population-based Rotterdam Study. Vascular risk factors (hypertension, hypercholesterolaemia, diabetes, obesity, physical inactivity and smoking) were assessed 13 (2004–2008) and 7 years (2009–2014) prior to 18F-florbetaben PET (2018–2021) in 635 dementia-free participants. Vascular risk factors were associated with binary amyloid PET status or continuous PET readouts (standard uptake value ratios, SUVrs) using logistic and linear regression models, respectively, adjusted for age, sex, education, APOE4 risk allele count and time between vascular risk and PET assessment. Participants’ mean age at time of amyloid PET was 69 years (range: 60–90), 325 (51.2%) were women and 190 (29.9%) carried at least one APOE4 risk allele. The adjusted prevalence estimates of an amyloid-positive PET status markedly increased with age [12.8% (95% CI 11.6; 14) in 60–69 years versus 35% (36; 40.8) in 80–89 years age groups] and APOE4 allele count [9.7% (8.8; 10.6) in non-carriers versus 38.4% (36; 40.8) to 60.4% (54; 66.8) in carriers of one or two risk allele(s)]. Diabetes 7 years prior to PET assessment was associated with a higher risk of a positive amyloid status [odds ratio (95% CI) = 3.68 (1.76; 7.61), P < 0.001] and higher standard uptake value ratios, indicating more severe Aβ pathology [standardized beta = 0.40 (0.17; 0.64), P = 0.001]. Hypertension was associated with higher SUVr values in APOE4 carriers (mean SUVr difference of 0.09), but not in non-carriers (mean SUVr difference 0.02; P = 0.005). In contrast, hypercholesterolaemia was related to lower SUVr values in APOE4 carriers (mean SUVr difference −0.06), but not in non-carriers (mean SUVr difference 0.02). Obesity, physical inactivity and smoking were not related to amyloid PET measures. The current findings suggest a contribution of diabetes, hypertension and hypercholesterolaemia to the pathophysiology of Alzheimer’s disease in a general population of older non-demented adults. As these conditions respond well to lifestyle modification and drug treatment, further research should focus on the preventative effect of early risk management on the development of Alzheimer’s disease neuropathology.

van Arendonk, Joyce (ORCID:0000000172941633)↗
DOE OSTI2023

Evaluation of Copper Chelation Therapy in a Transgenic Rat Model of Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of the amyloid β (Aβ) protein in blood vessels and leads to hemorrhages, strokes, and dementia in elderly individuals. Recent reports have shown elevated copper levels colocalized with vascular amyloid in human CAA and Alzheimer’s disease patients, which have been suggested to contribute to cytotoxicity through the formation of reactive oxygen species. Here, we treated a transgenic rat model of CAA (rTg-DI) with the copper-specific chelator, tetrathiomolybdate (TTM), via intraperitoneal (IP) administration for 6 months to determine if it could lower copper content in vascular amyloid deposits and modify CAA pathology. In this work, results showed that TTM treatment led to elevated Aβ load in the hippocampus of the rTg-DI rats and increased microbleeds in the wild type (WT) animals. X-ray fluorescence microscopy was performed to image the distribution of copper and revealed a surprising increase in copper colocalized with Aβ aggregates in TTM-treated rTg-DI rats. Unexpectedly, we also found an increase in the copper content in unaffected vessels of both rTg-DI and WT animals. These results show that IP administration of TTM was ineffective in removing copper from vascular Aβ aggregates in vivo and increased the development of disease pathology in CAA.

36 MATERIALS SCIENCE↗
DOE OSTI2022

A Hybrid Structural Method for Investigating Low Molecular Weight Oligomeric Structures of Amyloid Beta

Spurred in part by the failure of recent therapeutics targeting amyloid β plaques in Alzheimer's Disease (AD), attention is increasingly turning to the oligomeric forms of this peptide that form early in the aggregation process. However, while numerous amyloid β fibril structures have been characterized, primarily by NMR spectroscopy and cryo-EM, obtaining structural information on the low molecular weight forms of amyloid β that presumably precede and/or seed fibril formation has proved challenging. Furthermore, these transient forms are heterogeneous, and depend heavily on experimental conditions such as buffer, temperature, concentration, and degree of quiescence during measurement. Here, we present the concept for a new approach to delineating structural features of early-stage low molecular weight amyloid β oligomers, using a solvent accessibility assay in conjunction with simultaneous fluorescence measurements.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Structural polymorphism of amyloid fibrils in ATTR amyloidosis revealed by cryo-electron microscopy

ATTR amyloidosis is caused by the deposition of transthyretin in the form of amyloid fibrils in virtually every organ of the body, including the heart. This systemic deposition leads to a phenotypic variability that has not been molecularly explained yet. In brain amyloid conditions, previous studies suggest an association between clinical phenotype and the molecular structures of their amyloid fibrils. Here we investigate whether there is such an association in ATTRv amyloidosis patients carrying the mutation I84S. Using cryo-electron microscopy, we determined the structures of cardiac fibrils extracted from three ATTR amyloidosis patients carrying the ATTRv-I84S mutation, associated with a consistent clinical phenotype. We found that in each ATTRv-I84S patient, the cardiac fibrils exhibited different local conformations, and these variations can co-exist within the same fibril. Our finding suggests that one amyloid disease may associate with multiple fibril structures in systemic amyloidoses, calling for further studies.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

O-GlcNAc forces an α-synuclein amyloid strain with notably diminished seeding and pathology

Amyloid-forming proteins such α-synuclein and tau, which are implicated in Alzheimer’s and Parkinson’s disease, can form different fibril structures or strains with distinct toxic properties, seeding activities and pathology. Understanding the determinants contributing to the formation of different amyloid features could open new avenues for developing disease-specific diagnostics and therapies. Here we report that O-GlcNAc modification of α-synuclein monomers results in the formation of amyloid fibril with distinct core structure, as revealed by cryogenic electron microscopy, and diminished seeding activity in seeding-based neuronal and rodent models of Parkinson’s disease. Although the mechanisms underpinning the seeding neutralization activity of the O-GlcNAc-modified fibrils remain unclear, our in vitro mechanistic studies indicate that heat shock proteins interactions with O-GlcNAc fibril inhibit their seeding activity, suggesting that the O-GlcNAc modification may alter the interactome of the α-synuclein fibrils in ways that lead to reduce seeding activity in vivo. Our results show that posttranslational modifications, such as O-GlcNAc modification, of α-synuclein are key determinants of α-synuclein amyloid strains and pathogenicity.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
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 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↗