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2.
J Alzheimers Dis ; 85(4): 1573-1582, 2022.
Article in English | MEDLINE | ID: covidwho-1745159

ABSTRACT

BACKGROUND: Subjective cognitive decline (SCD), an at-risk condition of Alzheimer's disease (AD), can involve various cognitive domains, such as memory, language, planning, and attention. OBJECTIVE: We aim to explore the difference in amyloid load between the single memory domain SCD (sd-SCD) and the multidomain SCD (md-SCD) and assess the relationship of amyloid pathology with quantitative SCD scores and objective cognition. METHODS: A total of 63 SCD participants from the SILCODE study underwent the clinical evaluation, neuropsychological assessment, and 18F-florbetapir PET scan. Global amyloid standard uptake value ratio (SUVr) was calculated. Additionally, regional amyloid SUVr was quantified in 12 brain regions of interests. A nonparametric rank ANCOVA was used to compare the global and regional amyloid SUVr between the md-SCD (n = 34) and sd-SCD (n = 29) groups. A multiple linear regression analysis was conducted to test the relationship of amyloid SUVr with quantitative SCD scores and objective cognition. RESULTS: Compared with individuals with sd-SCD, individuals with md-SCD had increased global amyloid SUVr (F = 5.033, p = 0.029) and regional amyloid SUVr in the left middle temporal gyrus (F = 12.309, p = 0.001; Bonferroni corrected), after controlling for the effects of age, sex, and education. When pooling all SCD participants together, the increased global amyloid SUVr was related with higher SCD-plus sum scores and lower Auditory Verbal Learning Test-delayed recall scores. CONCLUSION: According to our findings, individuals with md-SCD showed higher amyloid accumulation than individuals with sd-SCD, suggesting that md-SCD may experience a more advanced stage of SCD. Additionally, increased global amyloid load was predictive of a poorer episodic memory function in SCD individuals.


Subject(s)
Amyloid/metabolism , Cognitive Dysfunction/pathology , Aged , Brain/pathology , Female , Humans , Male , Neuropsychological Tests/statistics & numerical data , Positron-Emission Tomography
3.
Biochem J ; 479(4): 537-559, 2022 02 17.
Article in English | MEDLINE | ID: covidwho-1705036

ABSTRACT

Post-acute sequelae of COVID (PASC), usually referred to as 'Long COVID' (a phenotype of COVID-19), is a relatively frequent consequence of SARS-CoV-2 infection, in which symptoms such as breathlessness, fatigue, 'brain fog', tissue damage, inflammation, and coagulopathies (dysfunctions of the blood coagulation system) persist long after the initial infection. It bears similarities to other post-viral syndromes, and to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Many regulatory health bodies still do not recognize this syndrome as a separate disease entity, and refer to it under the broad terminology of 'COVID', although its demographics are quite different from those of acute COVID-19. A few years ago, we discovered that fibrinogen in blood can clot into an anomalous 'amyloid' form of fibrin that (like other ß-rich amyloids and prions) is relatively resistant to proteolysis (fibrinolysis). The result, as is strongly manifested in platelet-poor plasma (PPP) of individuals with Long COVID, is extensive fibrin amyloid microclots that can persist, can entrap other proteins, and that may lead to the production of various autoantibodies. These microclots are more-or-less easily measured in PPP with the stain thioflavin T and a simple fluorescence microscope. Although the symptoms of Long COVID are multifarious, we here argue that the ability of these fibrin amyloid microclots (fibrinaloids) to block up capillaries, and thus to limit the passage of red blood cells and hence O2 exchange, can actually underpin the majority of these symptoms. Consistent with this, in a preliminary report, it has been shown that suitable and closely monitored 'triple' anticoagulant therapy that leads to the removal of the microclots also removes the other symptoms. Fibrin amyloid microclots represent a novel and potentially important target for both the understanding and treatment of Long COVID and related disorders.


Subject(s)
Amyloid , Anticoagulants/therapeutic use , COVID-19 , Lung , SARS-CoV-2/metabolism , Thrombosis , Amyloid/blood , Amyloid/chemistry , COVID-19/blood , COVID-19/drug therapy , Fibrin/chemistry , Fibrin/metabolism , Humans , Lung/metabolism , Lung/virology , Thrombosis/drug therapy , Thrombosis/metabolism , Thrombosis/virology
4.
ACS Chem Neurosci ; 13(1): 143-150, 2022 01 05.
Article in English | MEDLINE | ID: covidwho-1637498

ABSTRACT

First cases that point at a correlation between SARS-CoV-2 infections and the development of Parkinson's disease (PD) have been reported. Currently, it is unclear if there is also a direct causal link between these diseases. To obtain first insights into a possible molecular relation between viral infections and the aggregation of α-synuclein protein into amyloid fibrils characteristic for PD, we investigated the effect of the presence of SARS-CoV-2 proteins on α-synuclein aggregation. We show, in test tube experiments, that SARS-CoV-2 spike protein (S-protein) has no effect on α-synuclein aggregation, while SARS-CoV-2 nucleocapsid protein (N-protein) considerably speeds up the aggregation process. We observe the formation of multiprotein complexes and eventually amyloid fibrils. Microinjection of N-protein in SH-SY5Y cells disturbed the α-synuclein proteostasis and increased cell death. Our results point toward direct interactions between the N-protein of SARS-CoV-2 and α-synuclein as molecular basis for the observed correlation between SARS-CoV-2 infections and Parkinsonism.


Subject(s)
Amyloid , Coronavirus Nucleocapsid Proteins/metabolism , alpha-Synuclein , Amyloid/metabolism , COVID-19 , Humans , Phosphoproteins/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , alpha-Synuclein/metabolism
5.
Int J Biol Macromol ; 197: 68-76, 2022 Feb 01.
Article in English | MEDLINE | ID: covidwho-1587673

ABSTRACT

The C-terminal domain of SARS-CoV main protease (Mpro-C) can form 3D domain-swapped dimer by exchanging the α1-helices fully buried inside the protein hydrophobic core, under non-denaturing conditions. Here, we report that Mpro-C can also form amyloid fibrils under the 3D domain-swappable conditions in vitro, and the fibrils are not formed through runaway/propagated domain swapping. It is found that there are positive correlations between the rates of domain swapping dimerization and amyloid fibrillation at different temperatures, and for different mutants. However, some Mpro-C mutants incapable of 3D domain swapping can still form amyloid fibrils, indicating that 3D domain swapping is not essential for amyloid fibrillation. Furthermore, NMR H/D exchange data and molecular dynamics simulation results suggest that the protofibril core region tends to unpack at the early stage of 3D domain swapping, so that the amyloid fibrillation can proceed during the 3D domain swapping process. We propose that 3D domain swapping makes it possible for the unpacking of the amyloidogenic fragment of the protein and thus accelerates the amyloid fibrillation process kinetically, which explains the well-documented correlations between amyloid fibrillation and 3D domain swapping observed in many proteins.


Subject(s)
Amyloid/chemistry , Amyloid/metabolism , Amyloidosis/metabolism , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Protein Domains/physiology , Amyloidosis/genetics , Coronavirus 3C Proteases/genetics , Dimerization , Disulfides/chemistry , Disulfides/metabolism , Kinetics , Models, Molecular , Molecular Dynamics Simulation , Mutation , Polymerization , Protein Conformation, alpha-Helical , Protein Domains/genetics , Protein Folding , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Temperature
6.
J Phys Chem B ; 125(32): 9155-9167, 2021 08 19.
Article in English | MEDLINE | ID: covidwho-1347913

ABSTRACT

A marker for the severeness and disease progress of COVID-19 is overexpression of serum amyloid A (SAA) to levels that in other diseases are associated with a risk for SAA amyloidosis. To understand whether SAA amyloidosis could also be a long-term risk of SARS-CoV-2 infections, we have used long all-atom molecular dynamic simulations to study the effect of a SARS-CoV-2 protein segment on SAA amyloid formation. Sampling over 40 µs, we find that the presence of the nine-residue segment SK9, located at the C-terminus of the envelope protein, increases the propensity for SAA fibril formation by three mechanisms: it reduces the stability of the lipid-transporting hexamer shifting the equilibrium toward monomers, it increases the frequency of aggregation-prone configurations in the resulting chains, and it raises the stability of SAA fibrils. Our results therefore suggest that SAA amyloidosis and related pathologies may be a long-term risk of SARS-CoV-2 infections.


Subject(s)
Amyloidosis , COVID-19 , Amyloid , Humans , SARS-CoV-2 , Serum Amyloid A Protein
7.
Biosci Rep ; 41(8)2021 08 27.
Article in English | MEDLINE | ID: covidwho-1334001

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection, the cause of coronavirus disease 2019 (COVID-19), is characterized by unprecedented clinical pathologies. One of the most important pathologies, is hypercoagulation and microclots in the lungs of patients. Here we study the effect of isolated SARS-CoV-2 spike protein S1 subunit as potential inflammagen sui generis. Using scanning electron and fluorescence microscopy as well as mass spectrometry, we investigate the potential of this inflammagen to interact with platelets and fibrin(ogen) directly to cause blood hypercoagulation. Using platelet-poor plasma (PPP), we show that spike protein may interfere with blood flow. Mass spectrometry also showed that when spike protein S1 is added to healthy PPP, it results in structural changes to ß and γ fibrin(ogen), complement 3, and prothrombin. These proteins were substantially resistant to trypsinization, in the presence of spike protein S1. Here we suggest that, in part, the presence of spike protein in circulation may contribute to the hypercoagulation in COVID-19 positive patients and may cause substantial impairment of fibrinolysis. Such lytic impairment may result in the persistent large microclots we have noted here and previously in plasma samples of COVID-19 patients. This observation may have important clinical relevance in the treatment of hypercoagulability in COVID-19 patients.


Subject(s)
COVID-19/pathology , Fibrin/metabolism , Fibrinolysis/physiology , Spike Glycoprotein, Coronavirus/metabolism , Thrombosis/pathology , Adult , Aged , Amyloid/metabolism , Blood Platelets/metabolism , Complement C3/metabolism , Female , Fibrinogen/metabolism , Humans , Lung/pathology , Male , Microfluidic Analytical Techniques , Middle Aged , Prothrombin/metabolism , SARS-CoV-2/metabolism , Thrombosis/virology , Trypsin/metabolism
8.
Cells ; 10(7)2021 07 13.
Article in English | MEDLINE | ID: covidwho-1314588

ABSTRACT

Transthyretin (TTR) is a tetrameric protein transporting hormones in the plasma and brain, which has many other activities that have not been fully acknowledged. TTR is a positive indicator of nutrition status and is negatively correlated with inflammation. TTR is a neuroprotective and oxidative-stress-suppressing factor. The TTR structure is destabilized by mutations, oxidative modifications, aging, proteolysis, and metal cations, including Ca2+. Destabilized TTR molecules form amyloid deposits, resulting in senile and familial amyloidopathies. This review links structural stability of TTR with the environmental factors, particularly oxidative stress and Ca2+, and the processes involved in the pathogenesis of TTR-related diseases. The roles of TTR in biomineralization, calcification, and osteoarticular and cardiovascular diseases are broadly discussed. The association of TTR-related diseases and vascular and ligament tissue calcification with TTR levels and TTR structure is presented. It is indicated that unaggregated TTR and TTR amyloid are bound by vicious cycles, and that TTR may have an as yet undetermined role(s) at the crossroads of calcification, blood coagulation, and immune response.


Subject(s)
Arthritis/metabolism , Cardiovascular Diseases/metabolism , Osteoporosis/metabolism , Prealbumin/metabolism , Amyloid/chemistry , Amyloid/metabolism , Amyloidosis/metabolism , Animals , Humans , Oxidative Stress , Prealbumin/chemistry , Protein Conformation , Protein Stability
9.
Nat Nanotechnol ; 16(8): 918-925, 2021 08.
Article in English | MEDLINE | ID: covidwho-1260944

ABSTRACT

Minimizing the spread of viruses in the environment is the first defence line when fighting outbreaks and pandemics, but the current COVID-19 pandemic demonstrates how difficult this is on a global scale, particularly in a sustainable and environmentally friendly way. Here we introduce and develop a sustainable and biodegradable antiviral filtration membrane composed of amyloid nanofibrils made from food-grade milk proteins and iron oxyhydroxide nanoparticles synthesized in situ from iron salts by simple pH tuning. Thus, all the membrane components are made of environmentally friendly, non-toxic and widely available materials. The membrane has outstanding efficacy against a broad range of viruses, which include enveloped, non-enveloped, airborne and waterborne viruses, such as SARS-CoV-2, H1N1 (the influenza A virus strain responsible for the swine flu pandemic in 2009) and enterovirus 71 (a non-enveloped virus resistant to harsh conditions, such as highly acidic pH), which highlights a possible role in fighting the current and future viral outbreaks and pandemics.


Subject(s)
Amyloid/chemistry , Antiviral Agents/pharmacology , Ferric Compounds/chemistry , Micropore Filters , Nanoparticles/chemistry , Amyloid/pharmacology , Antiviral Agents/chemistry , Ferric Compounds/pharmacology , Humans , Lactoglobulins/chemistry , Micropore Filters/virology , Virus Inactivation/drug effects , Viruses/classification , Viruses/drug effects , Viruses/isolation & purification , Water Purification
10.
Orphanet J Rare Dis ; 16(1): 204, 2021 05 06.
Article in English | MEDLINE | ID: covidwho-1219017

ABSTRACT

BACKGROUND: The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causing the ongoing coronavirus disease 2019 (COVID-19) pandemic has raised serious concern for patients with chronic disease. A correlation has been identified between the severity of COVID-19 and a patient's preexisting comorbidities. Although COVID-19 primarily involves the respiratory system, dysfunction in multiple organ systems is common, particularly in the cardiovascular, gastrointestinal, immune, renal, and nervous systems. Patients with amyloid transthyretin (ATTR) amyloidosis represent a population particularly vulnerable to COVID-19 morbidity due to the multisystem nature of ATTR amyloidosis. MAIN BODY: ATTR amyloidosis is a clinically heterogeneous progressive disease, resulting from the accumulation of amyloid fibrils in various organs and tissues. Amyloid deposition causes multisystem clinical manifestations, including cardiomyopathy and polyneuropathy, along with gastrointestinal symptoms and renal dysfunction. Given the potential for exacerbation of organ dysfunction, physicians note possible unique challenges in the management of patients with ATTR amyloidosis who develop multiorgan complications from COVID-19. While the interplay between COVID-19 and ATTR amyloidosis is still being evaluated, physicians should consider that the heightened susceptibility of patients with ATTR amyloidosis to multiorgan complications might increase their risk for poor outcomes with COVID-19. CONCLUSION: Patients with ATTR amyloidosis are suspected to have a higher risk of morbidity and mortality due to age and underlying ATTR amyloidosis-related organ dysfunction. While further research is needed to characterize this risk and management implications, ATTR amyloidosis patients might require specialized management if they develop COVID-19. The risks of delaying diagnosis or interrupting treatment for patients with ATTR amyloidosis should be balanced with the risk of exposure in the health care setting. Both physicians and patients must adapt to a new construct for care during and possibly after the pandemic to ensure optimal health for patients with ATTR amyloidosis, minimizing treatment interruptions.


Subject(s)
Amyloid Neuropathies, Familial , COVID-19 , Amyloid , Humans , Pandemics , Prealbumin , SARS-CoV-2
11.
Trends Microbiol ; 29(11): 967-969, 2021 11.
Article in English | MEDLINE | ID: covidwho-1157751

ABSTRACT

Severe coronavirus disease 2019 (COVID-19) infection leads to multifactorial acute respiratory distress syndrome (ARDS), with little therapeutic success. The pathophysiology associated with ARDS or post-ARDS is not yet well understood. We hypothesize that amyloid formation occurring due to protein homeostasis disruption can be one of the complications associated with COVID-19-induced-ARDS.


Subject(s)
Amyloid/metabolism , COVID-19/complications , COVID-19/virology , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/metabolism , SARS-CoV-2 , Amyloidosis/etiology , Amyloidosis/metabolism , Amyloidosis/pathology , Animals , Disease Management , Disease Susceptibility , Humans , Respiratory Distress Syndrome/diagnosis
12.
Biochem Biophys Res Commun ; 554: 94-98, 2021 05 21.
Article in English | MEDLINE | ID: covidwho-1157142

ABSTRACT

The post-infection of COVID-19 includes a myriad of neurologic symptoms including neurodegeneration. Protein aggregation in brain can be considered as one of the important reasons behind the neurodegeneration. SARS-CoV-2 Spike S1 protein receptor binding domain (SARS-CoV-2 S1 RBD) binds to heparin and heparin binding proteins. Moreover, heparin binding accelerates the aggregation of the pathological amyloid proteins present in the brain. In this paper, we have shown that the SARS-CoV-2 S1 RBD binds to a number of aggregation-prone, heparin binding proteins including Aß, α-synuclein, tau, prion, and TDP-43 RRM. These interactions suggests that the heparin-binding site on the S1 protein might assist the binding of amyloid proteins to the viral surface and thus could initiate aggregation of these proteins and finally leads to neurodegeneration in brain. The results will help us to prevent future outcomes of neurodegeneration by targeting this binding and aggregation process.


Subject(s)
Amyloid/metabolism , COVID-19/metabolism , Heparin/metabolism , Neurodegenerative Diseases/metabolism , Protein Aggregation, Pathological , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/metabolism , Amyloid beta-Peptides/metabolism , Brain/metabolism , Brain/pathology , Brain/virology , COVID-19/virology , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/metabolism , Humans , Molecular Docking Simulation , Neurodegenerative Diseases/virology , Prions/metabolism , Protein Binding , SARS-CoV-2/chemistry , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , alpha-Synuclein/metabolism , tau Proteins/metabolism
13.
Cardiovasc Diabetol ; 19(1): 193, 2020 11 17.
Article in English | MEDLINE | ID: covidwho-925887

ABSTRACT

BACKGROUND: Type 2 Diabetes Mellitus (T2DM) is a well-known comorbidity to COVID-19 and coagulopathies are a common accompaniment to both T2DM and COVID-19. In addition, patients with COVID-19 are known to develop micro-clots within the lungs. The rapid detection of COVID-19 uses genotypic testing for the presence of SARS-Cov-2 virus in nasopharyngeal swabs, but it can have a poor sensitivity. A rapid, host-based physiological test that indicated clotting severity and the extent of clotting pathologies in the individual who was infected or not would be highly desirable. METHODS: Platelet poor plasma (PPP) was collected and frozen. On the day of analysis, PPP samples were thawed and analysed. We show here that microclots can be detected in the native plasma of twenty COVID-19, as well as ten T2DM patients, without the addition of any clotting agent, and in particular that such clots are amyloid in nature as judged by a standard fluorogenic stain. Results were compared to ten healthy age-matched individuals. RESULTS: In COVID-19 plasma these microclots are significantly increased when compared to the levels in T2DM. CONCLUSIONS: This fluorogenic test may provide a rapid and convenient test with 100% sensitivity (P < 0.0001) and is consistent with the recognition that the early detection and prevention of such clotting can have an important role in therapy.


Subject(s)
Amyloid/blood , COVID-19/blood , Diabetes Mellitus, Type 2/blood , SARS-CoV-2 , Thrombosis/blood , COVID-19/epidemiology , Diabetes Mellitus, Type 2/epidemiology , Female , Humans , Male , Middle Aged , Prevalence , Thrombosis/epidemiology
14.
Amyloid ; 27(4): 217-222, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-889371

ABSTRACT

The ISA Nomenclature Committee met electronically before and directly after the XVII ISA International Symposium on Amyloidosis, which, unfortunately, had to be virtual in September 2020 due to the ongoing COVID-19 pandemic instead of a planned meeting in Tarragona in March. In addition to confirmation of basic nomenclature, several additional concepts were discussed, which are used in scientific amyloid literature. Among such concepts are cytotoxic oligomers, protofibrils, primary and secondary nucleation, seeding and cross-seeding, amyloid signature proteins, and amyloid plaques. Recommendations for their use are given. Definitions of amyloid and amyloidosis are confirmed. Possible novel human amyloid fibril proteins, appearing as 'classical' in vivo amyloid, were discussed. It was decided to include fibulin-like extracellular matrix protein 1 (amyloid protein: AEFEMP1), which appears as localised amyloid in portal veins. There are several possible amyloid proteins under investigation, and these are included in a new Table.


Subject(s)
Amyloid/classification , Amyloidogenic Proteins/classification , Amyloidosis/classification , Terminology as Topic , Amyloid/genetics , Amyloid/metabolism , Amyloidogenic Proteins/genetics , Amyloidogenic Proteins/metabolism , Amyloidosis/diagnosis , Amyloidosis/genetics , Amyloidosis/pathology , COVID-19 , Congresses as Topic , Coronavirus Infections , Education, Distance/organization & administration , Gene Expression , Humans , Pandemics , Pneumonia, Viral
15.
J Am Chem Soc ; 142(40): 17024-17038, 2020 10 07.
Article in English | MEDLINE | ID: covidwho-772998

ABSTRACT

Broad-spectrum antivirals are powerful weapons against dangerous viruses where no specific therapy exists, as in the case of the ongoing SARS-CoV-2 pandemic. We discovered that a lysine- and arginine-specific supramolecular ligand (CLR01) destroys enveloped viruses, including HIV, Ebola, and Zika virus, and remodels amyloid fibrils in semen that promote viral infection. Yet, it is unknown how CLR01 exerts these two distinct therapeutic activities. Here, we delineate a novel mechanism of antiviral activity by studying the activity of tweezer variants: the "phosphate tweezer" CLR01, a "carboxylate tweezer" CLR05, and a "phosphate clip" PC. Lysine complexation inside the tweezer cavity is needed to antagonize amyloidogenesis and is only achieved by CLR01. Importantly, CLR01 and CLR05 but not PC form closed inclusion complexes with lipid head groups of viral membranes, thereby altering lipid orientation and increasing surface tension. This process disrupts viral envelopes and diminishes infectivity but leaves cellular membranes intact. Consequently, CLR01 and CLR05 display broad antiviral activity against all enveloped viruses tested, including herpesviruses, Measles virus, influenza, and SARS-CoV-2. Based on our mechanistic insights, we potentiated the antiviral, membrane-disrupting activity of CLR01 by introducing aliphatic ester arms into each phosphate group to act as lipid anchors that promote membrane targeting. The most potent ester modifications harbored unbranched C4 units, which engendered tweezers that were approximately one order of magnitude more effective than CLR01 and nontoxic. Thus, we establish the mechanistic basis of viral envelope disruption by specific tweezers and establish a new class of potential broad-spectrum antivirals with enhanced activity.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Bridged-Ring Compounds/pharmacology , Organophosphates/pharmacology , Viral Envelope Proteins/drug effects , Acid Phosphatase/chemistry , Acid Phosphatase/metabolism , Amyloid/antagonists & inhibitors , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Arginine/chemistry , Betacoronavirus/drug effects , Bridged-Ring Compounds/chemistry , Cell Membrane/chemistry , Cell Membrane/drug effects , Cell Membrane/virology , HIV Infections/drug therapy , HIV-1/drug effects , Humans , Lipids/chemistry , Lysine/chemistry , Magnetic Resonance Spectroscopy , Organophosphates/chemistry , SARS-CoV-2 , Seminal Vesicle Secretory Proteins/chemistry , Seminal Vesicle Secretory Proteins/metabolism , Structure-Activity Relationship , Viral Envelope Proteins/metabolism , Zika Virus/drug effects
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