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1.
Braz J Med Biol Res ; 53(6): e8625, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32428129

RESUMO

Amyloidosis comprises a group of disorders that accumulate modified autologous proteins in organs, mainly the kidneys. Few studies have addressed the amyloid compartmental distribution and associated clinical outcomes. The aim of this study was to present a case series of renal amyloidosis correlating histopathological data with glomerular filtration rate (GFR) during kidney biopsy. We studied 53 cases reviewed by nephropathologists from 2000 to 2018 in a single kidney biopsy center in Brazil. GFR was estimated using the CKD-EPI formula. Cases were divided into Group A ≥60 and Group B <60 mL·min-1·(1.73 m2)-1 using the estimated GFR during kidney biopsy. Semiquantitative histopathological study was performed, including extension and distribution of amyloid deposits by compartments (glomeruli, tubulointerstitial tissue, and vessels). Statistical analyses were made to understand associations with lower GFR. No difference was seen for age, gender, proteinuria, hematuria, subtype of amyloid protein, arteriosclerosis, interstitial fibrosis/infiltrate, or glomerular and interstitial amyloid deposits. After a previous P value <0.1 in the descriptive analysis, the following variables were selected: globally sclerotic glomeruli, high blood pressure, and the extension of vascular amyloid deposition. A binary logistic regression model with GFR as the dependent variable showed history of hypertension and vascular amyloid to be robust and independent predictors of Group B <60 mL·min-1·(1.73 m2)-1. Beyond the histopathologic diagnosis of amyloidosis, a semiquantitative approach on renal biopsy could provide new insights. Vascular amyloid is an independent predictor of renal dysfunction in cases of renal amyloidosis.


Assuntos
Amiloide/fisiologia , Amiloidose/patologia , Taxa de Filtração Glomerular , Nefropatias/patologia , Rim/patologia , Adulto , Idoso , Amiloidose/fisiopatologia , Biópsia , Feminino , Humanos , Rim/fisiopatologia , Nefropatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
2.
Medicine (Baltimore) ; 99(16): e19620, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32311931

RESUMO

For the diagnosis of mild cognitive impairment (MCI) and Alzheimer disease (AD), variable neuroimaging and neuropsychological tests have been used. We aimed to evaluate the correlation of neuropsychological domain with new amyloid positron emission tomography (PET) study and to validate the availability of new PET tracer.We enrolled 20 patients who underwent C-PiB-PET/CT, new PET tracer F-FC119S PET/CT from November, 2014 to July, 2015. Among them, 10 patients were diagnosed with AD and 10 patients with MCI. The current version of Seoul Neuropsychological Screening Battery (SNSB) II was performed for cognitive evaluation. Each parameter of SNSB was compared between 2 patient groups. Spearman correlation analysis between value of SNSB domain and standardized uptake value ratio (SUVR) of PET was also performed.The AD group presented significant poor z-score in Korean-Boston Naming Test(K-BNT) (P = .01),copy score of Rey Complex Figure Test (RCFT) (P = .049), immediate (P = .028)and delayed memory of Seoul Verbal Learning Test (SVLT) (P = .028), recognition of RCFT (P = .004), "animal" of Controlled Oral Word Association Test (COWAT) (P = .041), color reading of Korean-Color Word Stroop test (K-CWST) (P = .014), and Digit Symbol Coding (DSC) (P = .007) compared with MCI group. That means, except attention domain, all other cognitive domains were relatively impaired in AD compared with MCI. In correlation analysis, we found that poor performances on copy score of RCFT in MCI groups were associated with great beta amyloid burden in frontal area in both C-PiB-PET/CT and F-FC119S PET/CT. In AD group, F-FC119S PET presented more extensive correlation in each cognitive domain with multiple cortical areas compared with C-PiB-PET.The degree of amyloid burden assessed on F-FC119S PET was significantly correlated with neuropsychological test in AD, and also MCI patients. The combination of neuropsychological evaluation with novel F-FC119S PET/CT can be used for valid biomarker for MCI and AD.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Amiloide/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Compostos de Anilina , Radioisótopos de Carbono , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/psicologia , Feminino , Radioisótopos de Flúor , Humanos , Masculino , Pessoa de Meia-Idade , Neuroimagem/métodos , Testes Neuropsicológicos , Traçadores Radioativos , Tiazóis
3.
Phys Rev Lett ; 124(11): 118102, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32242730

RESUMO

The fine interplay between the simultaneous stretching and confinement of amyloid fibrils is probed by combining a microcapillary setup with atomic force microscopy. Single-molecule statistics reveal how the stretching of fibrils changed from force to confinement dominated at different length scales. System order, however, is solely ruled by confinement. Coarse-grained simulations support the results and display the potential to tailor system properties by tuning the two effects. These findings may further help shed light on in vivo amyloid fibril growth and transport in highly confined environments such as blood vessels.


Assuntos
Amiloide/química , Modelos Químicos , Amiloide/metabolismo , Simulação por Computador , Microscopia de Força Atômica/métodos
4.
Nat Med ; 26(3): 398-407, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32161412

RESUMO

Development of tau-based therapies for Alzheimer's disease requires an understanding of the timing of disease-related changes in tau. We quantified the phosphorylation state at multiple sites of the tau protein in cerebrospinal fluid markers across four decades of disease progression in dominantly inherited Alzheimer's disease. We identified a pattern of tau staging where site-specific phosphorylation changes occur at different periods of disease progression and follow distinct trajectories over time. These tau phosphorylation state changes are uniquely associated with structural, metabolic, neurodegenerative and clinical markers of disease, and some (p-tau217 and p-tau181) begin with the initial increases in aggregate amyloid-ß as early as two decades before the development of aggregated tau pathology. Others (p-tau205 and t-tau) increase with atrophy and hypometabolism closer to symptom onset. These findings provide insights into the pathways linking tau, amyloid-ß and neurodegeneration, and may facilitate clinical trials of tau-based treatments.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Padrões de Herança/genética , Proteínas tau/metabolismo , Adulto , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Atrofia , Encéfalo/patologia , Cognição , Progressão da Doença , Feminino , Fluordesoxiglucose F18/química , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Fosforilação , Placa Amiloide/patologia , Solubilidade , Proteínas tau/líquido cefalorraquidiano
5.
Nat Med ; 26(3): 387-397, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32123386

RESUMO

With the potential development of new disease-modifying Alzheimer's disease (AD) therapies, simple, widely available screening tests are needed to identify which individuals, who are experiencing symptoms of cognitive or behavioral decline, should be further evaluated for initiation of treatment. A blood-based test for AD would be a less invasive and less expensive screening tool than the currently approved cerebrospinal fluid or amyloid ß positron emission tomography (PET) diagnostic tests. We examined whether plasma tau phosphorylated at residue 181 (pTau181) could differentiate between clinically diagnosed or autopsy-confirmed AD and frontotemporal lobar degeneration. Plasma pTau181 concentrations were increased by 3.5-fold in AD compared to controls and differentiated AD from both clinically diagnosed (receiver operating characteristic area under the curve of 0.894) and autopsy-confirmed frontotemporal lobar degeneration (area under the curve of 0.878). Plasma pTau181 identified individuals who were amyloid ß-PET-positive regardless of clinical diagnosis and correlated with cortical tau protein deposition measured by 18F-flortaucipir PET. Plasma pTau181 may be useful to screen for tau pathology associated with AD.


Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Degeneração Lobar Frontotemporal/sangue , Degeneração Lobar Frontotemporal/diagnóstico , Proteínas tau/sangue , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Amiloide/metabolismo , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Cognição , Feminino , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/patologia , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Proteínas de Neurofilamentos/sangue , Fosforilação , Tomografia por Emissão de Pósitrons , Índice de Gravidade de Doença , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/genética
6.
Subcell Biochem ; 94: 421-436, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32189310

RESUMO

As normal constituents of blood serum, the Serum Amyloid A (SAA) proteins are small (104 amino acids in humans) and remarkably well-conserved in mammalian evolution. They are synthesized prominently, but not exclusively, in the liver. Fragments of SAA can associate into insoluble fibrils (called "amyloid") characteristic of "secondary" amyloid disease in which they can interrupt normal physiology and lead to organ failure. SAA proteins comprise a family of molecules, two members of which (SAA1 and SAA2) are (along with C-reactive protein, CRP) the most prominent members of the acute phase response (APR) during which their serum levels rise dramatically after trauma, infection and other stimuli. Biologic function (s) of SAA are unresolved but features are consistent with a prominent role in primordial host defense (including the APR ). SAA proteins are lipophilic and contribute to high density lipoproteins (HDL) and cholesterol transport. SAA proteins interact with specific receptors and have been implicated in tissue remodeling through metalloproteinases, local tissue changes in atherosclerosis, cancer metastasis, lung inflammation, maternal-fetal health and intestinal physiology. Molecular details of some of these are emerging.


Assuntos
Proteína Amiloide A Sérica , Reação de Fase Aguda , Amiloide/química , Amiloide/metabolismo , Animais , Colesterol/metabolismo , Doença , Humanos , Lipoproteínas HDL/metabolismo , Fígado/metabolismo , Proteína Amiloide A Sérica/química , Proteína Amiloide A Sérica/metabolismo
7.
Science ; 367(6483): 1230-1234, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32165583

RESUMO

How long-lived memories withstand molecular turnover is a fundamental question. Aggregates of a prion-like RNA-binding protein, cytoplasmic polyadenylation element-binding (CPEB) protein, is a putative substrate of long-lasting memories. We isolated aggregated Drosophila CPEB, Orb2, from adult heads and determined its activity and atomic structure, at 2.6-angstrom resolution, using cryo-electron microscopy. Orb2 formed ~75-nanometer-long threefold-symmetric amyloid filaments. Filament formation transformed Orb2 from a translation repressor to an activator and "seed" for further translationally active aggregation. The 31-amino acid protofilament core adopted a cross-ß unit with a single hydrophilic hairpin stabilized through interdigitated glutamine packing. Unlike the hydrophobic core of pathogenic amyloids, the hydrophilic core of Orb2 filaments suggests how some neuronal amyloids could be a stable yet regulatable substrate of memory.


Assuntos
Amiloide/química , Proteínas de Drosophila/química , Memória de Longo Prazo , Neurônios/metabolismo , Agregados Proteicos , Proteínas de Ligação a RNA/química , Fatores de Transcrição/química , Fatores de Poliadenilação e Clivagem de mRNA/química , Animais , Microscopia Crioeletrônica , Drosophila melanogaster , Glutamina/química , Interações Hidrofóbicas e Hidrofílicas , Conformação Proteica
8.
Nature ; 578(7794): 273-277, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32025029

RESUMO

Synucleinopathies are neurodegenerative diseases that are associated with the misfolding and aggregation of α-synuclein, including Parkinson's disease, dementia with Lewy bodies and multiple system atrophy1. Clinically, it is challenging to differentiate Parkinson's disease and multiple system atrophy, especially at the early stages of disease2. Aggregates of α-synuclein in distinct synucleinopathies have been proposed to represent different conformational strains of α-synuclein that can self-propagate and spread from cell to cell3-6. Protein misfolding cyclic amplification (PMCA) is a technique that has previously been used to detect α-synuclein aggregates in samples of cerebrospinal fluid with high sensitivity and specificity7,8. Here we show that the α-synuclein-PMCA assay can discriminate between samples of cerebrospinal fluid from patients diagnosed with Parkinson's disease and samples from patients with multiple system atrophy, with an overall sensitivity of 95.4%. We used a combination of biochemical, biophysical and biological methods to analyse the product of α-synuclein-PMCA, and found that the characteristics of the α-synuclein aggregates in the cerebrospinal fluid could be used to readily distinguish between Parkinson's disease and multiple system atrophy. We also found that the properties of aggregates that were amplified from the cerebrospinal fluid were similar to those of aggregates that were amplified from the brain. These findings suggest that α-synuclein aggregates that are associated with Parkinson's disease and multiple system atrophy correspond to different conformational strains of α-synuclein, which can be amplified and detected by α-synuclein-PMCA. Our results may help to improve our understanding of the mechanism of α-synuclein misfolding and the structures of the aggregates that are implicated in different synucleinopathies, and may also enable the development of a biochemical assay to discriminate between Parkinson's disease and multiple system atrophy.


Assuntos
Atrofia de Múltiplos Sistemas/diagnóstico , Doença de Parkinson/diagnóstico , alfa-Sinucleína/líquido cefalorraquidiano , alfa-Sinucleína/química , Amiloide/química , Química Encefálica , Dicroísmo Circular , Endopeptidase K/metabolismo , Humanos , Atrofia de Múltiplos Sistemas/líquido cefalorraquidiano , Doença de Parkinson/líquido cefalorraquidiano , Conformação Proteica , Desnaturação Proteica , Dobramento de Proteína , Espectroscopia de Infravermelho com Transformada de Fourier , alfa-Sinucleína/classificação , alfa-Sinucleína/toxicidade
9.
Proc Natl Acad Sci U S A ; 117(9): 4710-4717, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32071201

RESUMO

Peptide self-assembly, wherein molecule A associates with other A molecules to form fibrillar ß-sheet structures, is common in nature and widely used to fabricate synthetic biomaterials. Selective coassembly of peptide pairs A and B with complementary partial charges is gaining interest due to its potential for expanding the form and function of biomaterials that can be realized. It has been hypothesized that charge-complementary peptides organize into alternating ABAB-type arrangements within assembled ß-sheets, but no direct molecular-level evidence exists to support this interpretation. We report a computational and experimental approach to characterize molecular-level organization of the established peptide pair, CATCH. Discontinuous molecular dynamics simulations predict that CATCH(+) and CATCH(-) peptides coassemble but do not self-assemble. Two-layer ß-sheet amyloid structures predominate, but off-pathway ß-barrel oligomers are also predicted. At low concentration, transmission electron microscopy and dynamic light scattering identified nonfibrillar ∼20-nm oligomers, while at high concentrations elongated fibers predominated. Thioflavin T fluorimetry estimates rapid and near-stoichiometric coassembly of CATCH(+) and CATCH(-) at concentrations ≥100 µM. Natural abundance 13C NMR and isotope-edited Fourier transform infrared spectroscopy indicate that CATCH(+) and CATCH(-) coassemble into two-component nanofibers instead of self-sorting. However, 13C-13C dipolar recoupling solid-state NMR measurements also identify nonnegligible AA and BB interactions among a majority of AB pairs. Collectively, these results demonstrate that strictly alternating arrangements of ß-strands predominate in coassembled CATCH structures, but deviations from perfect alternation occur. Off-pathway ß-barrel oligomers are also suggested to occur in coassembled ß-strand peptide systems.


Assuntos
Amiloide/química , Nanofibras/química , Simulação por Computador , Polimerização , Conformação Proteica em Folha beta , Multimerização Proteica , Eletricidade Estática
10.
PLoS One ; 15(2): e0229319, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32084222

RESUMO

Biomolecular self-assembly is an emerging bottom-up approach for the synthesis of novel nanomaterials. DNA and viruses have both been used to create scaffolds but the former lacks chemical diversity and the latter lack spatial control. To date, the use of protein scaffolds to template materials on the nanoscale has focused on amyloidogenic proteins that are known to form fibrils or two-protein systems where a second protein acts as a cross-linker. We previously developed a unique approach for self-assembly of nanomaterials based on engineering ß-solenoid proteins (BSPs) to polymerize into micrometer-length fibrils. BSPs have highly regular geometries, tunable lengths, and flat surfaces that are amenable to engineering and functionalization. Here, we present a newly engineered BSP based on the antifreeze protein of the beetle Rhagium inquisitor (RiAFP-m9), which polymerizes into stable fibrils under benign conditions. Gold nanoparticles were used to functionalize the RiAFP-m9 fibrils as well as those assembled from the previously described SBAFP-m1 protein. Cysteines incorporated into the sequences provide site-specific gold attachment. Additionally, silver was deposited on the gold-labelled fibrils by electroless plating to create nanowires. These results bolster prospects for programable self-assembly of BSPs to create scaffolds for functional nanomaterials.


Assuntos
Amiloide/metabolismo , Proteínas Anticongelantes/metabolismo , Ouro/química , Proteínas de Insetos/metabolismo , Nanopartículas Metálicas/química , Nanotecnologia/métodos , Engenharia de Proteínas/métodos , Amiloide/química , Animais , Besouros , Simulação de Dinâmica Molecular
11.
Chem Commun (Camb) ; 56(21): 3147-3150, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32057047

RESUMO

Amyloid fibrils, implicated in health and diseases, commonly exhibit a periodic twist trait relevant to the structures and dynamics of the fibrils. However, the origins and modulations of fibril twist in complex in vivo environments are not yet fully understood. Here we highlight an important factor that causes twist variations in amyloid fibril structures-the presence of surrounding surfaces. Using cholesterol-containing lipid bilayers with varying cholesterol contents, we have demonstrated via atomic force microscopy that amyloid-ß peptide fibrils initiated on membranes increase their average pitch size of twisting periodicity as the cholesterol content increases. These surface-induced twist variations arise from the enhanced hydrophobic interactions between the fibril and the surface distorting the torsional elastic energy of the fibril twisting as supported by a theory of an elastic model. These findings not only provide an important insight into fibril polymorphism phenomena resulting from the surface effects but also suggest a novel solution to modulate filament twisting on the nanoscale for biomaterials applications involving nanoscale features.


Assuntos
Amiloide/química , Colesterol/química , Bicamadas Lipídicas/química , Microscopia de Força Atômica , Tamanho da Partícula , Conformação Proteica , Propriedades de Superfície
12.
Nat Commun ; 11(1): 1007, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-32081907

RESUMO

Bacterial biofilms, especially those associated with implanted medical devices, are difficult to eradicate. Curli amyloid fibers are important components of the biofilms formed by the Enterobacteriaceae family. Here, we show that a human monoclonal antibody with pan-amyloid-binding activity (mAb 3H3) can disrupt biofilms formed by Salmonella enterica serovar Typhimurium in vitro and in vivo. The antibody disrupts the biofilm structure, enhancing biofilm eradication by antibiotics and immune cells. In mice, 3H3 injections allow antibiotic-mediated clearance of catheter-associated S. Typhimurium biofilms. Thus, monoclonal antibodies that bind a pan-amyloid epitope have potential to prevent or eradicate bacterial biofilms.


Assuntos
Amiloide/imunologia , Proteínas de Bactérias/imunologia , Biofilmes/crescimento & desenvolvimento , Salmonella typhimurium/imunologia , Salmonella typhimurium/fisiologia , Animais , Anticorpos Monoclonais/imunologia , Infecções Relacionadas a Cateter/prevenção & controle , Epitopos/imunologia , Humanos , Macrófagos/imunologia , Camundongos , Infecções por Salmonella/prevenção & controle
13.
PLoS One ; 15(2): e0229137, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32053667

RESUMO

IMPORTANCE: Clinical guidelines currently recommend against amyloid imaging for cognitively unimpaired persons. The goal of Alzheimer's disease (AD) prevention, together with advances in understanding the pathophysiology of AD, however, has led to trials testing drugs in cognitively unimpaired persons who show evidence of AD biomarkers. Assuming the eventual success of such trials, millions of patients will be affected. There is a need to understand the effects of biomarker disclosure on those individuals. DESIGN: The Study of Knowledge and Reactions to Amyloid Testing (SOKRATES) involved 2 semi-structured telephone interviews with individuals who received amyloid PET scan results as part of screening for research participation. Post-disclosure interviews were conducted at 4 to 12 weeks and again 1 year later. Data were collected from November 5, 2014 to November 30, 2016. Interviews were transcribed and coded in NVivo 12.0. PARTICIPANTS: 80 adults aged 65 and older: 50 who received "elevated" and 30 who received "not-elevated" amyloid PET scan results. MAIN OUTCOMES: Interviews examined four domains: (1) comprehension of the amyloid PET scan result; (2) implications of the result for sense of self, memory, and future; (3) sharing of results with others; and (4) AD risk-reduction behaviors. RESULTS: Participants who received an elevated amyloid PET scan result viewed the result as more serious and sensitive than other medical test results given its unique implications for identity, self-determination, and stigma. In contrast, participants who received a not-elevated amyloid PET scan result described feeling relief and reinterpreted perceived memory impairments as normal aging. Participants with elevated amyloid reported contemplating and making more changes to health behaviors and future plans than their peers with not-elevated amyloid. CONCLUSIONS: Clinical practice in the diagnosis and treatment of persons with preclinical AD, a stage of the disease defined by the presence of biomarkers in the absence of cognitive impairment, will need to address matters of identity, stigma, and life-planning.


Assuntos
Amiloide/metabolismo , Cognição , Revelação , Conhecimentos, Atitudes e Prática em Saúde , Tomografia por Emissão de Pósitrons , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/prevenção & controle , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Masculino
14.
Biochemistry ; 59(3): 315-328, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31898895

RESUMO

TDP-43 protein travels between the cytosol and the nucleus to perform its nucleic acid binding functions through its two tandem RNA recognition motif domains (TDP-43tRRM). When exposed to various environmental stresses, it forms abnormal aggregates in the cytosol of neurons, which are the hallmarks of amyotrophic lateral sclerosis and other TDP-43 proteinopathies. However, the nature of early structural changes upon stress sensing and the consequent steps during the course of aggregation are not well understood. In this study, we show that under low-pH conditions, mimicking starvation stress, TDP-43tRRM undergoes a conformational opening reaction linked to the protonation of buried ionizable residues and grows into a metastable oligomeric assembly (called the "low-pH form" or the "L form"). In the L form, the protein molecules have disrupted tertiary structure, solvent-exposed hydrophobic patches, and mobile side chains but the native-like secondary structure remains intact. The L form structure is held by weak interactions and has a steep dependence on ionic strength. In the presence of as little as 15 mM KCl, it fully misfolds and further oligomerizes to form a ß-sheet rich "ß form" in at least two distinct steps. The ß form has an ordered, stable structure that resembles worm-like amyloid fibrils. The unstructured regions of the protein gain structure during L ⇌ ß conversion. Our results suggest that TDP-43tRRM could function as a stress sensor and support a recent model in which stress sensing during neurodegeneration occurs by assembly of proteins into metastable assemblies that are precursors to the solid aggregates.


Assuntos
Amiloide/genética , Esclerose Amiotrófica Lateral/genética , Proteínas de Ligação a DNA/genética , Proteinopatias TDP-43/genética , Amiloide/química , Esclerose Amiotrófica Lateral/patologia , Fenômenos Biofísicos , Núcleo Celular/química , Núcleo Celular/genética , Citosol/química , Citosol/metabolismo , Proteínas de Ligação a DNA/química , Humanos , Agregados Proteicos/genética , Dobramento de Proteína , Estabilidade Proteica , Estrutura Secundária de Proteína/genética , Motivo de Reconhecimento de RNA/genética , Estresse Fisiológico/genética , Proteinopatias TDP-43/patologia
15.
Photochem Photobiol Sci ; 19(1): 29-33, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31932832

RESUMO

We demonstrate amyloid fibril (AF) decomposition induced by NIR-active upconversion nanoparticles complexed with photosensitisers. The process is triggered by upconversion, which initiates a photochemical reaction cascade that culminates in the generation of the highly reactive singlet-oxygen product 1O2 close to the amyloid superstructures, resulting in AF decomposition.


Assuntos
Amiloide/antagonistas & inibidores , Nanopartículas/química , Fármacos Fotossensibilizantes/farmacologia , Amiloide/metabolismo , Humanos , Raios Infravermelhos
16.
Neurology ; 94(8): e861-e873, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-31896617

RESUMO

OBJECTIVE: To distinguish between patients with amyloid-positive (A+) and -negative (A-) amnestic mild cognitive impairment (aMCI) by simultaneously investigating navigation performance, visual exploration behavior, and brain activations during a real-space navigation paradigm. METHODS: Twenty-one patients with aMCI were grouped into A+ (n = 11) and A- cases by amyloid-PET imaging and amyloid CSF levels and compared to 15 healthy controls. Neuropsychological deficits were quantified by use of the Consortium to Establish a Registry for Alzheimer's Disease-plus cognitive battery. All participants performed a navigation task in which they had to find items in a realistic spatial environment and had to apply egocentric and allocentric route planning strategies. 18F-fluorodeoxyglucose was injected at the start to detect navigation-induced brain activations. Subjects wore a gaze-controlled, head-fixed camera that recorded their visual exploration behavior. RESULTS: A+ patients performed worse during egocentric and allocentric navigation compared to A- patients and controls (p < 0.001). Both aMCI subgroups used fewer shortcuts, moved more slowly, and stayed longer at crossings. Word-list learning, figural learning, and Trail-Making tests did not differ in the A+ and A- subgroups. A+ patients showed a reduced activation of the right hippocampus, retrosplenial, and parietal cortex during navigation compared to A- patients (p < 0.005). CONCLUSIONS: A+ patients with aMCI perform worse than A- patients with aMCI in egocentric and allocentric route planning because of a more widespread impairment of their cerebral navigation network. Navigation testing in real space is a promising approach to identify patients with aMCI with underlying Alzheimer pathology.


Assuntos
Amnésia/fisiopatologia , Amiloide/líquido cefalorraquidiano , Disfunção Cognitiva/fisiopatologia , Navegação Espacial/fisiologia , Percepção Visual/fisiologia , Idoso , Amnésia/líquido cefalorraquidiano , Amnésia/complicações , Estudos de Casos e Controles , Córtex Cerebral/fisiopatologia , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/complicações , Feminino , Fluordesoxiglucose F18/metabolismo , Neuroimagem Funcional , Hipocampo/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons
17.
Brain Nerve ; 72(1): 23-34, 2020 Jan.
Artigo em Japonês | MEDLINE | ID: mdl-31907330

RESUMO

There is an urgent need for Alzheimer's disease (AD) treatments because of the growing number of individuals with preclinical, prodromal, and dementia forms of AD. Unfortunately, there are few effective treatments for AD, and many drug development trials for AD ultimately have failed. Current AD clinical trials include disease-modifying therapies, symptomatic cognitive enhancers, and symptomatic agents addressing neuropsychiatric and behavioral changes. Disease modifying therapies include anti-amyloid agents and anti-tau agents, both of which contain small molecules, monoclonal antibodies, or biological therapies. Amyloid is the most common specific target in phase 3 and phase 2 disease modification trials. Recent drug development trials for AD include preclinical and prodromal populations. Although biomarkers are increasingly used in drug development for AD, they are not used uniformly for confirmation of AD diagnosis. Enrollment of earlier populations, new biomarkers (e.g., neurofilament light), novel outcomes (e.g., AD Composite Score [ADCOMS]), and innovative trial designs (e.g., futility analysis, Bayesian adaptive designs) are needed to develop effective drugs against AD.


Assuntos
Doença de Alzheimer , Amiloide , Proteínas Amiloidogênicas , Teorema de Bayes , Biomarcadores , Humanos
18.
Chem Commun (Camb) ; 56(15): 2348-2351, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-31993621

RESUMO

A miniaturized mimic of the active site of a protease, chymotrypsin, was linked to a target recognition unit to generate "Miniature Artificial Proteases" (mAPs). Time-resolved MALDI-TOF data analyses indicated that mAPs cleaved every amide bond between Lys16-Phe20 of the amyloid ß fragment (Aß12-21) and Aß1-40, resulting in inhibition of fibrillization and disruption of the preformed amyloid. Such a platform may offer not only new therapeutic options against various amyloidoses but also novel routes for the selective knockdown of specific proteins.


Assuntos
Amiloide/metabolismo , Quimotripsina/metabolismo , Amiloide/química , Domínio Catalítico , Quimotripsina/química , Humanos , Modelos Moleculares , Estrutura Molecular
20.
Nat Commun ; 11(1): 347, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953405

RESUMO

In Alzheimer's diseases (AD), tau pathology is strongly associated with cognitive decline. Preclinical evidence suggests that tau spreads across connected neurons in an activity-dependent manner. Supporting this, cross-sectional AD studies show that tau deposition patterns resemble functional brain networks. However, whether higher functional connectivity is associated with higher rates of tau accumulation is unclear. Here, we combine resting-state fMRI with longitudinal tau-PET in two independent samples including 53 (ADNI) and 41 (BioFINDER) amyloid-biomarker defined AD subjects and 28 (ADNI) vs. 16 (BioFINDER) amyloid-negative healthy controls. In both samples, AD subjects show faster tau accumulation than controls. Second, in AD, higher fMRI-assessed connectivity between 400 regions of interest (ROIs) is associated with correlated tau-PET accumulation in corresponding ROIs. Third, we show that a model including baseline connectivity and tau-PET is associated with future tau-PET accumulation. Together, connectivity is associated with tau spread in AD, supporting the view of transneuronal tau propagation.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Amiloide , Biomarcadores , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Disfunção Cognitiva , Estudos Transversais , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Tomografia por Emissão de Pósitrons
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