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Mollee, Peter, Patricia Renaut, Samuel Boros, Dorothy Loo et Michelle Hill. « Diagnosis of Amyloidosis Subtype By Laser-Capture Microdissection (LCM) and Tandem Mass Spectrometry (MS/MS) Proteomic Analysis ». Blood 126, no 23 (3 décembre 2015) : 1779. http://dx.doi.org/10.1182/blood.v126.23.1779.1779.
Texte intégralRésumé :
Abstract Aim Correct identification of the protein that is causing amyloidosis is crucial for clinical management. Current standard laboratory methods have limited ability to detect the full range of amyloid forming proteins. We assessed the diagnostic value of LCM-MS/MS, which combines specific sampling of amyloid deposits by LCM with protein identification by MS/MS. Methods Biopsy specimens were referred to the Princess Alexandra Hospital Amyloidosis Centre. For all specimens, 10µm sections of formalin-fixed paraffin embedded tissue were stained with Congo Red using a standard technique. LCM was performed using an Arcturus XT instrument with an infrared capture laser. Proteins were extracted with FFPE Protein Extraction Solution (Agilent Technologies), digested with trypsin and peptides were analysed by nano-liquid chromatography-coupled MS/MS using an Agilent Chip CUBE-QTOF. Database searching was performed using Spectrum Mill (Agilent) with the NCBInr human protein database. Results Biopsies were received on 136 patients: there was insufficient tissue in the block in 7, repeat LCM was required in15 cases and no amyloid forming protein was identified in 8. In 121/136 (89%) an amyloid forming protein was identified. Proteins identified included immunoglobulin light chain (localised amyloid n=25, systemic AL n=45), immunoglobulin heavy chain (AH n=6), transthyretin (senile amyloid n=25, hereditary ATTR n=6), serum amyloid A (AA n=7), fibrinogen alpha chain (AFib n=2), LECT2 (ALect2 n=2), TGFb (corneal lattice amyloid n=1) and semenogelin (seminal vesicle amyloid n=2). It was not infrequent, particularly in cases of localised amyloidosis (>80% of cases), for smaller amounts of other amyloid forming proteins to be present especially immunoglobulins, transthyretin and ApoA1 (Table 1). This suggests that these inherently amyloidogenic proteins are capable of integrating within the amyloid deposit. An amyloid proteomic signature as previously defined by the Mayo Clinic (at least two of SAP, ApoE and ApoA4; Haematologica 2014;99(7):1239) was present in 76% of cases and was more likely to be found if larger amounts of amyloid could be dissected (p=0.0001). In terms of clinical impact, amyloid typing by immunohistochemical stains had been attempted in 87 cases and reported as diagnostic in 39. Five of these were subsequently revealed by proteomic analysis to be incorrect. Overall, the clinical diagnosis of amyloid subtype was altered by proteomic analysis in 24% of cases. Conclusion. LCMMS/MS identifies an amyloid forming protein in ~90% of clinical biopsy samples. Amyloid deposits often contain small amounts of other amyloid forming proteins which may reflect not just contamination but co-deposition of fibrils due to a shared beta pleated sheet conformation. Because of this, results need to be interpreted in the context of full clinical information to enable correct diagnosis of amyloid subtype. Table 1. LCM-MS/MS results Amyloidosis subtype AL-lambda AL-kappa AH Localised lambda Localised kappa ATTRwt ATTRmut AA Number of subtype cases 32 13 5 16 9 25 6 7 Amyloid forming proteins Lambda light chain 32 16 1 2 Kappa light chain 4 13 2 5 9 4 1 Ig heavy chain 8 5 6 6 4 1 3 Transthyretin 1 3 3 25 6 ApoA1 2 3 7 3 SAA 7 Fibrinogen alpha chain 2 1 2 1 Lysozyme 1 1 1 Cases with low levels of 2nd amyloid forming protein 34% 46% 40% 81% 89% 20% 17% 57% Amyloid associated proteins ApoE 21 12 2 16 7 19 6 5 SAP 16 8 13 6 24 6 4 ApoA4 23 10 1 16 8 22 6 2 Amyloid proteomic signature 63% 77% 0% 100% 78% 92% 100% 57% Disclosures Mollee: Onyx: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.
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Radko, S. P., S. A. Khmeleva, E. V. Suprun, S. A. Kozin, N. V. Bodoev, A. A. Makarov, A. I. Archakov et V. V. Shumyantseva. « Physico-chemical methods for studing beta-amyloid aggregation ». Biomeditsinskaya Khimiya 61, no 2 (2015) : 203–18. http://dx.doi.org/10.18097/pbmc20156102203.
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Alzheimer's disease is the most prevalent neurodegenerative pathology. According to the amyloid cascade hypothesis, a key event of the Alzheimer's disease pathogenesis is a transition of the b-amyloid peptide (Аb) from the monomeric form to the aggregated state. The mechanism of Аb aggregation is intensively studied in vitro, by means of synthetic peptides and various physico-chemical methods allowing evaluation of size, molecular structure, and morphology of the formed aggregates. The paper reviews both the well-known and recently introduced physico-chemical methods for analysis of Аb aggregation, including microscopу, optical and fluorescent methods, method of electron paramagnetic resonance, electrochemical and electrophoretic methods, gel-filtration, and mass spectrometric methods. Merits and drawbacks of the methods are discussed. The unique possibility to simultaneously observe Аb monomers as well oligomers and large aggregates by means of atomic force microscopy or fluorescence correlation spectroscopy is emphasized. The high detection sensitivity of the latter method, monitoring the aggregation process in Аb solutions at low peptide concentrations is underlined. Among mass spectrometric methods, the ion mobility mass spectrometry is marked out as a method enabling to obtain information about both the spectrum of Аb oligomers and their structure. It is pointed out that the use of several methods giving the complementary data about Аb aggregates is the best experimental approach to studying the process of b-amyloid peptide aggregation in vitro.
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Bourbouli, Mara, Michael Rentzos, Anastasia Bougea, Vasiliki Zouvelou, Vasilios C. Constantinides, Ioannis Zaganas, Ioannis Evdokimidis, Elisabeth Kapaki et George P. Paraskevas. « Cerebrospinal Fluid TAR DNA-Binding Protein 43 Combined with Tau Proteins as a Candidate Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Spectrum Disorders ». Dementia and Geriatric Cognitive Disorders 44, no 3-4 (2017) : 144–52. http://dx.doi.org/10.1159/000478979.
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Background: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are nowadays recognized as spectrum disorders with a molecular link, the TAR DNA-binding protein 43 (TDP-43), rendering it a surrogate biomarker for these disorders. Methods: We measured cerebrospinal fluid (CSF) levels of TDP-43, beta-amyloid peptide with 42 amino acids (Aβ42), total tau protein (τT), and tau protein phosphorylated at threonine 181 (τP-181) in 32 patients with ALS, 51 patients with FTD, and 17 healthy controls. Double-sandwich commercial enzyme-linked immunosorbent assays were used for measurements. Results: Both ALS and FTD patients presented with higher TDP-43 and τT levels compared to the control group. The combination of biomarkers in the form of the TDP-43 × τT / τP-181 formula achieved the best discrimination between ALS or FTD and controls, with sensitivities and specificities >0.8. Conclusion: Combined analysis of TDP-43, τT, and τP-181 in CSF may be useful for the antemortem diagnosis of ALS and FTD.
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Mollee, Peter, Patricia Renaut, Samuel Boros, Dorothy Loo et Michelle Hill. « Diagnosis Of Amyloidosis Subtype By Laser-Capture Microdissection (LCM) and Tandem Mass Spectrometry (MS) Proteomic Analysis ». Blood 122, no 21 (15 novembre 2013) : 5295. http://dx.doi.org/10.1182/blood.v122.21.5295.5295.
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Abstract Aim Correct identification of the protein that is causing amyloidosis is crucial for clinical management. Current standard diagnostic methods have limited ability to detect the full range of amyloid forming proteins. We assessed combining specific sampling of amyloid deposits by LCM and analysis of tryptic digests by tandem MS proteomic analysis to determine whether the majority of amyloidosis clinical samples can be correctly classified as reported by the Mayo Clinic pathology department. Methods We studied 58 cases of well characterised amyloid deposition and 10 cases in which the amyloid subtype was unable to be diagnosed with confidence. For all specimens, 10µm sections of formalin-fixed paraffin embedded tissue were stained with Congo Red using a standard technique. LCM was performed using an Arcturus XT instrument with an infrared capture laser. Proteins were digested with trypsin and peptides were analysed by nano-liquid chromatography-coupled tandem mass spectrometry using a Chip CUBE-QTOF. Database searching was performed using Spectrum Mill (Agilent) with the NCBInr human protein database. Protein identification cut-offs were protein score > 11, peptide score > 10 and % scored peak intensity >60. Results Biopsy sites included: GIT (n=16), cardiac (n=12), soft tissue (n=8), renal (n=9), liver (n=3) and other (n=20). The amyloid subtype was able to be determined in 64 cases analysed. In 7 of these cases a second sample or second LCM was required as the first analysis was non-diagnostic. In 4 cases the amyloidogenic protein was not identified mostly due to the amyloid deposits being very small. Proteins identified included immunoglobulin light chain (localised amyloid n=6, systemic AL n=32), transthyretin (senile amyloid n=17, hereditary ATTR n=2), serum amyloid A (AA n=4), fibrinogen (AFib n=1), TGFb (corneal lattice amyloid n=1) and semenogelin (seminal vesicle amyloid n=1). Three diagnostically challenging cases are detailed as examples of the utility of LCM and tandem MS. The first case had extensive gastrointestinal amyloidosis and no evidence of clonal light chain disease; negative kappa, lambda, SAA and transthyretin immunohistochemistry; and negative genetic studies. Tandem MS revealed immunoglobulin lambda light chain type. The second diagnostically challenging case had: isolated renal amyloidosis with a positive AA stain and kappa restricted serum free light chains. Tandem MS revealed serum amyloid A2 protein. The third case had: cardiac, neurological and gastrointestinal involvement; and equivocal immunohistochemistry. Tandem MS demonstrated transthyretin and genetic studies showed a A97S ATTR mutation. Various other proteins were identified by tandem MS in amyloid extracts. Of particular interest is the presence of proteins typically known to be co-located in amyloid deposits which helps confirm that the microdissected tissue is amyloid. Typical amyloid-associated proteins were identified in the following number of cases: SAP (n=36), apolipoprotein A4 (n=42), vitronectin (n=44), apolipoprotein E (n=40) and clusterin (n=21). Various types of collagen were frequently present (n=29) and various, presumably contaminating, keratins were identified (n=24). Conclusion LCM and tandem MS allows correct typing of amyloid deposits in the majority of clinical biopsy samples. Disclosures: No relevant conflicts of interest to declare.
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Hasani, Seyede Anis, Mahsa Mayeli, Mohammad Amin Salehi et Rezvan Barzegar Parizi. « A Systematic Review of the Association between Amyloid-β and τ Pathology with Functional Connectivity Alterations in the Alzheimer Dementia Spectrum Utilizing PET Scan and rsfMRI ». Dementia and Geriatric Cognitive Disorders Extra 11, no 2 (6 mai 2021) : 78–90. http://dx.doi.org/10.1159/000516164.
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The association between functional connectivity (FC) alterations with amyloid-β (Aβ) and τ protein depositions in Alzheimer dementia is a subject of debate in the current literature. Although many studies have suggested a declining FC accompanying increased Aβ and τ concentrations, some investigations have contradicted this hypothesis. Therefore, this systematic review was conducted to sum up the current literature in this regard. The PROSPERO guideline for systematic reviews was applied for development of a research protocol, and this study was initiated after getting the protocol approval. Studies were screened, and those investigating FC measured by resting-state functional MRI and Aβ and τ protein depositions using amyloid and τ positron emission tomography were included. We categorized the included studies into 3 groups methodologically, addressing the question using global connectivity analysis (examining all regions of interest across the brain based on a functional atlas), seed-based connectivity analysis, or within-networks connectivity analysis. The quality of the studies was assessed using the Newcastle-Ottawa Scale. Among 31 included studies, 14 found both positive and negative correlations depending on the brain region and stage of the investigated disease, while 7 showed an overall negative correlation, 8 indicated an overall positive correlation, and 2 found a nonsignificant association between protein deposition and FC. The investigated regions were illustrated using tables. The posterior default mode network, one of the first regions of amyloid accumulation, and the temporal lobe, the early τ deposition region, are the 2 most investigated regions where inconsistencies exist. In conclusion, our study indicates that transneuronal spreading of τ and the amyloid hypothesis can justify higher FC related to higher protein depositions when global connectivity analysis is applied. However, the discrepancies observed when investigating the brain locally could be due to the varying manifestations of the amyloid and τ overload compensatory mechanisms in the brain at different stages of the disease with hyper- and hypoconnectivity cycles that can occur repeatedly. Nevertheless, further studies investigating both amyloid and τ deposition simultaneously while considering the stage of Alzheimer dementia are required to assess the accuracy of this hypothesis.
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D'Souza, Anita, Jason D. Theis, Julie A. Vrana et Ahmet Dogan. « Drug-Induced Amyloidosis : A Proteomic Insight Into 52 Cases ». Blood 122, no 21 (15 novembre 2013) : 1871. http://dx.doi.org/10.1182/blood.v122.21.1871.1871.
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Abstract The amyloidoses are heterogeneous diseases associated with the deposition of insoluble proteins or peptides with a characteristic beta-diffraction pattern extracellularly. At the current time, over 27 different extracellular fibril proteins are known to cause disease in humans. Iatrogenic amyloidosis is a rare, often not sought diagnosis. On occasion, patients with drug induced amyloidosis can present with other systemic features reminiscent of systemic immunoglobulin-derived (AL) amyloidosis, and may present a diagnostic challenge. Treatment of the latter often involves chemotherapy and/or stem cell transplantation, while the former tends to remain localized and needs local therapy; thus accurate diagnosis is critical. To this end, proteomic analysis of amyloid tissue has proven to be an invaluable tool in amyloid typing. We have analyzed the biochemical composition of iatrogenic amyloid using laser capture/tandem mass spectrometry (LC-MS/MS)-based proteomic analysis in 52 cases of insulin and enfuvirtide (Fuzeon¨) associated amyloidosis. In brief, 10-μm-thick sections of formalin-fixed paraffin-embedded tissues were stained with Congo red. Congo red positively staining tissue as viewed with a fluorescent light source appeared bright red. Positive areas were dissected using laser microdissection to a volume of at least 60,000 μm2; three microdissections were analyzed for each case. The microdissected material was collected into 0.5-ml microcentrifuge tube caps containing 35 μL Tris/EDTA/0.002% Zwittergent buffer. Microdissected fragments were subjected to a heat-mediated antigen retrieval method (98C for 90minutes) before being denatured via sonication and subsequently digested into tryptic peptides overnight using 0.5ug of trypsin. The resulting digests were then analyzed with nanoflow LC-MS/MS. The MS/MS spectra of each case were matched against a composite protein sequence database using three different search algorithms (Sequest, X!Tandem, and Mascot). The composite database contained the human SwissProt entries but was also augmented with known immunoglobulin variant domains, known amyloidogenic mutations from literature, the enfuvirtide amino acid sequence, and common contaminants. Reversed protein sequences were appended to the database for estimating the false discovery rates of the identifications. The peptide identification results were filtered using Scaffold software (Proteome Software, Portland, OR) and then filtered peptides were assembled into protein identifications. Candidate proteins with at least one high-confident (probability of identification >90%) unique peptide identification and at least four MS/MS spectral matches were considered for clinical interpretation. For each case, we created a personalized proteomic profile that lists all the confident protein identifications in each of the microdissection along with their respective MS/MS spectral counts. The number of MS/MS spectra matching to a protein is considered as a semi-quantitative measure of its abundance. The most abundant amyloidogenic protein detected across all microdissections and as interpreted in the context of the clinical history is considered to be the amyloid subtype. Figure 1 shows the results of insulin amyloidosis. Figure 2 shows the results of enfuvirtide amyloidosis. Amyloid deposits are shown to be composed of the recombinant drug in addition to amyloid precursor proteins such as apolipoprotein A-I, A-IV, E and serum amyloid P (SAP).Figure 1. Insulin-associated amyloidosisFigure 1. Insulin-associated amyloidosisFigure 2Enfuvirtide (Fuzeon¨)-associated amyloidosisFigure 2. Enfuvirtide (Fuzeon¨)-associated amyloidosis In conclusion, we show the biochemical composition of all known drug-induced iatrogenic amyloidosis and provide the utility of proteomic analysis in elucidating amyloid subtyping for accurate diagnosis and management. Legend: A spectral count number of greater than 4 is significant. The green boxes denote protein identification at a probability of over 95%, and yellow 80-94%. In figure 1, insulin (# 2) and in figure 2, enfuvirtide (#5) are shown in abundance, additionally other amyloid precursors such as apolipoproteins A-IV, E, A-I and SAP are also seen. Disclosures: No relevant conflicts of interest to declare.
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Micsonai, András, Frank Wien, Linda Kernya, Young-Ho Lee, Yuji Goto, Matthieu Réfrégiers et József Kardos. « Accurate secondary structure prediction and fold recognition for circular dichroism spectroscopy ». Proceedings of the National Academy of Sciences 112, no 24 (2 juin 2015) : E3095—E3103. http://dx.doi.org/10.1073/pnas.1500851112.
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Circular dichroism (CD) spectroscopy is a widely used technique for the study of protein structure. Numerous algorithms have been developed for the estimation of the secondary structure composition from the CD spectra. These methods often fail to provide acceptable results on α/β-mixed or β-structure–rich proteins. The problem arises from the spectral diversity of β-structures, which has hitherto been considered as an intrinsic limitation of the technique. The predictions are less reliable for proteins of unusual β-structures such as membrane proteins, protein aggregates, and amyloid fibrils. Here, we show that the parallel/antiparallel orientation and the twisting of the β-sheets account for the observed spectral diversity. We have developed a method called β-structure selection (BeStSel) for the secondary structure estimation that takes into account the twist of β-structures. This method can reliably distinguish parallel and antiparallel β-sheets and accurately estimates the secondary structure for a broad range of proteins. Moreover, the secondary structure components applied by the method are characteristic to the protein fold, and thus the fold can be predicted to the level of topology in the CATH classification from a single CD spectrum. By constructing a web server, we offer a general tool for a quick and reliable structure analysis using conventional CD or synchrotron radiation CD (SRCD) spectroscopy for the protein science research community. The method is especially useful when X-ray or NMR techniques fail. Using BeStSel on data collected by SRCD spectroscopy, we investigated the structure of amyloid fibrils of various disease-related proteins and peptides.
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Qin, Qiu, Ronghua Song, Peng Du, Chaoqun Gao, Qiuming Yao et Jin-an Zhang. « Systemic Proteomic Analysis Reveals Distinct Exosomal Protein Profiles in Rheumatoid Arthritis ». Journal of Immunology Research 2021 (18 août 2021) : 1–11. http://dx.doi.org/10.1155/2021/9421720.
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Objective. Rheumatoid arthritis (RA) is a complex disease with unknown pathogenesis. In recent years, fewer have paid attention to the broad spectrum of systemic markers of RA. The aim of this study was to identify exosomal candidate proteins in the pathogenesis of RA. Methods. Totally, 12 specimens of plasma from 6 RA patients and 6 age- and gender-matched controls from the Chinese population were obtained for nanoscale liquid chromatography coupled to tandem mass spectrometry (nano-LC-MS/MS) analysis to identify exosomal profiles. Results. A total of 278 exosomal proteins were detected. Among them, 32 proteins were significantly upregulated ( FC ≥ 2.0 and P < 0.05 ) and 5 proteins were downregulated ( FC ≤ 0.5 and P < 0.05 ). Bioinformatics analysis revealed that transthyretin (TTR), angiotensinogen (AGT), lipopolysaccharide-binding protein (LBP), monocyte differentiation antigen CD14 (CD14), cartilage oligomeric matrix protein (COMP), serum amyloid P (SAP/APCS), and tenascin (TNC) can interact with each other. Subsequently, these cross-linked proteins may be mainly involved in the inflammatory-related pathways to mediate the onset of RA. Noteworthy, the LBP/CD14 complex can promote the expression of IL-8 and TNF-α, eventually leading to the development of RA. Conclusions. Our findings suggest distinct plasmatic exosomal protein profiles in RA patients. These proteins not only take important parts in the vicious circle in the pathogenic process of RA but also serve as novel biomarkers in RA diagnosis and prognosis.
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Bell, Lauren N., Lydia Lee, Romil Saxena, Kerry G. Bemis, Mu Wang, Janice L. Theodorakis, Raj Vuppalanchi, Mouhamad Alloosh, Michael Sturek et Naga Chalasani. « Serum proteomic analysis of diet-induced steatohepatitis and metabolic syndrome in the Ossabaw miniature swine ». American Journal of Physiology-Gastrointestinal and Liver Physiology 298, no 5 (mai 2010) : G746—G754. http://dx.doi.org/10.1152/ajpgi.00485.2009.
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We recently developed a nutritional model of steatohepatitis and metabolic syndrome in Ossabaw pigs. Here we describe changes in the serum proteome of pigs fed standard chow (control group; n = 7), atherogenic diet ( n = 5), or modified atherogenic diet (M-ath diet group; n = 6). Pigs fed atherogenic diet developed metabolic syndrome and mildly abnormal liver histology, whereas pigs fed M-ath diet exhibited severe metabolic syndrome and liver injury closely resembling human nonalcoholic steatohepatitis (NASH). Using a label-free mass spectrometry-based proteomics approach, we identified 1,096 serum proteins, 162 of which changed significantly between any two diet groups (false discovery rate <5%). Biological classification of proteins with significant changes revealed functions previously implicated in development of NASH in humans, including immune system regulation and inflammation (orosomucoid 1, serum amyloid P component, paraoxonase 1, protein similar to α-2-macroglobulin precursor, β-2-microglobulin, p101 protein, and complement components 2 and C8G), lipid metabolism (apolipoproteins C-III, E, E precursor, B, and N), structural and extracellular matrix proteins (transthyretin and endopeptidase 24.16 type M2), and coagulation [carboxypeptidase B2 (plasma)]. Several proteins with significant differential expression in pigs were also identified in our recent human proteomics study as changing significantly in serum from patients across the spectrum of nonalcoholic fatty liver disease, including apolipoproteins C-III and B, orosomucoid 1, serum amyloid P component, transthyretin, paraoxonase 1, and a protein similar to α-2-macroglobulin precursor. This serum proteomic analysis provides additional information about the pathogenesis of NASH and further characterizes our large animal model of diet-induced steatohepatitis and metabolic syndrome in Ossabaw pigs.
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Bevan-Jones, W. Richard, Thomas E. Cope, P. Simon Jones, Sanne S. Kaalund, Luca Passamonti, Kieren Allinson, Oliver Green et al. « Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum ». Brain 143, no 3 (1 mars 2020) : 1010–26. http://dx.doi.org/10.1093/brain/awaa033.
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Abstract The clinical syndromes of frontotemporal dementia are clinically and neuropathologically heterogeneous, but processes such as neuroinflammation may be common across the disease spectrum. We investigated how neuroinflammation relates to the localization of tau and TDP-43 pathology, and to the heterogeneity of clinical disease. We used PET in vivo with (i) 11C-PK-11195, a marker of activated microglia and a proxy index of neuroinflammation; and (ii) 18F-AV-1451, a radioligand with increased binding to pathologically affected regions in tauopathies and TDP-43-related disease, and which is used as a surrogate marker of non-amyloid-β protein aggregation. We assessed 31 patients with frontotemporal dementia (10 with behavioural variant, 11 with the semantic variant and 10 with the non-fluent variant), 28 of whom underwent both 18F-AV-1451 and 11C-PK-11195 PET, and matched control subjects (14 for 18F-AV-1451 and 15 for 11C-PK-11195). We used a univariate region of interest analysis, a paired correlation analysis of the regional relationship between binding distributions of the two ligands, a principal component analysis of the spatial distributions of binding, and a multivariate analysis of the distribution of binding that explicitly controls for individual differences in ligand affinity for TDP-43 and different tau isoforms. We found significant group-wise differences in 11C-PK-11195 binding between each patient group and controls in frontotemporal regions, in both a regions-of-interest analysis and in the comparison of principal spatial components of binding. 18F-AV-1451 binding was increased in semantic variant primary progressive aphasia compared to controls in the temporal regions, and both semantic variant primary progressive aphasia and behavioural variant frontotemporal dementia differed from controls in the expression of principal spatial components of binding, across temporal and frontotemporal cortex, respectively. There was a strong positive correlation between 11C-PK-11195 and 18F-AV-1451 uptake in all disease groups, across widespread cortical regions. We confirmed this association with post-mortem quantification in 12 brains, demonstrating strong associations between the regional densities of microglia and neuropathology in FTLD-TDP (A), FTLD-TDP (C), and FTLD-Pick's. This was driven by amoeboid (activated) microglia, with no change in the density of ramified (sessile) microglia. The multivariate distribution of 11C-PK-11195 binding related better to clinical heterogeneity than did 18F-AV-1451: distinct spatial modes of neuroinflammation were associated with different frontotemporal dementia syndromes and supported accurate classification of participants. These in vivo findings indicate a close association between neuroinflammation and protein aggregation in frontotemporal dementia. The inflammatory component may be important in shaping the clinical and neuropathological patterns of the diverse clinical syndromes of frontotemporal dementia.
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Lin, Chin-Hsien, Shu-I. Chiu, Ta-Fu Chen, Jyh-Shing Roger Jang et Ming-Jang Chiu. « Classifications of Neurodegenerative Disorders Using a Multiplex Blood Biomarkers-Based Machine Learning Model ». International Journal of Molecular Sciences 21, no 18 (21 septembre 2020) : 6914. http://dx.doi.org/10.3390/ijms21186914.
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Easily accessible biomarkers for Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal dementia (FTD), and related neurodegenerative disorders are urgently needed in an aging society to assist early-stage diagnoses. In this study, we aimed to develop machine learning algorithms using the multiplex blood-based biomarkers to identify patients with different neurodegenerative diseases. Plasma samples (n = 377) were obtained from healthy controls, patients with AD spectrum (including mild cognitive impairment (MCI)), PD spectrum with variable cognitive severity (including PD with dementia (PDD)), and FTD. We measured plasma levels of amyloid-beta 42 (Aβ42), Aβ40, total Tau, p-Tau181, and α-synuclein using an immunomagnetic reduction-based immunoassay. We observed increased levels of all biomarkers except Aβ40 in the AD group when compared to the MCI and controls. The plasma α-synuclein levels increased in PDD when compared to PD with normal cognition. We applied machine learning-based frameworks, including a linear discriminant analysis (LDA), for feature extraction and several classifiers, using features from these blood-based biomarkers to classify these neurodegenerative disorders. We found that the random forest (RF) was the best classifier to separate different dementia syndromes. Using RF, the established LDA model had an average accuracy of 76% when classifying AD, PD spectrum, and FTD. Moreover, we found 83% and 63% accuracies when differentiating the individual disease severity of subgroups in the AD and PD spectrum, respectively. The developed LDA model with the RF classifier can assist clinicians in distinguishing variable neurodegenerative disorders.
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Takomthong, Pitchayakarn, Pornthip Waiwut, Chavi Yenjai, Bungon Sripanidkulchai, Prasert Reubroycharoen, Ren Lai, Peter Kamau et Chantana Boonyarat. « Structure–Activity Analysis and Molecular Docking Studies of Coumarins from Toddalia asiatica as Multifunctional Agents for Alzheimer’s Disease ». Biomedicines 8, no 5 (2 mai 2020) : 107. http://dx.doi.org/10.3390/biomedicines8050107.
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Coumarins, naturally occurring phytochemicals, display a wide spectrum of biological activities by acting on multiple targets. Herein, nine coumarins from the root of Toddalia asiatica were evaluated for activities related to pathogenesis of Alzheimer’s disease (AD). They were examined for acetylcholinesterase (AChE) and AChE- or self-induced amyloid beta (Aβ) aggregation inhibitory activities, as well as neuroprotection against H2O2- and Aβ1–42-induced human neuroblastoma SH-SY5Y cell damage. Moreover, in order to understand the mechanism, the binding interactions between coumarins and their targets: (i) AChE and (ii) Aβ1–42 peptide were investigated in silico. All coumarins exhibited mild to moderate AChE and self-induced Aβ aggregation inhibitory actions. In addition, the coumarins substituted with the long alkyl chain at position 6 or 8 illustrated ability to inhibit AChE-induced Aβ aggregation, resulting from their dual binding site at catalytic anionic site and peripheral active site in AChE. Moreover, the most potent multifunctional coumarin, phellopterin, could attenuate neuronal cell damage induced by H2O2 and Aβ1–42 toxicity. Conclusively, seven out of nine coumarins were identified as multifunctional agents inhibiting the pathogenesis of AD. The structure–activity relationship information obtained might be applied for further optimization of coumarins into a useful drug which may combat AD.
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Gong, Ping, Kulandaivelu S. Vetrivel, Phuong D. Nguyen, Xavier Meckler, Haipeng Cheng, Maria Z. Kounnas, Steven L. Wagner, Angèle T. Parent et Gopal Thinakaran. « Mutation Analysis of the Presenilin 1 N-terminal Domain Reveals a Broad Spectrum of γ-Secretase Activity toward Amyloid Precursor Protein and Other Substrates ». Journal of Biological Chemistry 285, no 49 (4 octobre 2010) : 38042–52. http://dx.doi.org/10.1074/jbc.m110.132613.
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Erickson, Craig A., Balmiki Ray, Bryan Maloney, Logan K. Wink, Katherine Bowers, Tori L. Schaefer, Christopher J. McDougle, Deborah K. Sokol et Debomoy K. Lahiri. « Impact of acamprosate on plasma amyloid-β precursor protein in youth : A pilot analysis in fragile X syndrome-associated and idiopathic autism spectrum disorder suggests a pharmacodynamic protein marker ». Journal of Psychiatric Research 59 (décembre 2014) : 220–28. http://dx.doi.org/10.1016/j.jpsychires.2014.07.011.
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Hendrix, James A., David C. Airey, Angela Britton, Anna D. Burke, George T. Capone, Ronelyn Chavez, Jacqueline Chen et al. « Cross-Sectional Exploration of Plasma Biomarkers of Alzheimer’s Disease in Down Syndrome : Early Data from the Longitudinal Investigation for Enhancing Down Syndrome Research (LIFE-DSR) Study ». Journal of Clinical Medicine 10, no 9 (28 avril 2021) : 1907. http://dx.doi.org/10.3390/jcm10091907.
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With improved healthcare, the Down syndrome (DS) population is both growing and aging rapidly. However, with longevity comes a very high risk of Alzheimer’s disease (AD). The LIFE-DSR study (NCT04149197) is a longitudinal natural history study recruiting 270 adults with DS over the age of 25. The study is designed to characterize trajectories of change in DS-associated AD (DS-AD). The current study reports its cross-sectional analysis of the first 90 subjects enrolled. Plasma biomarkers phosphorylated tau protein (p-tau), neurofilament light chain (NfL), amyloid β peptides (Aβ1-40, Aβ1-42), and glial fibrillary acidic protein (GFAP) were undertaken with previously published methods. The clinical data from the baseline visit include demographics as well as the cognitive measures under the Severe Impairment Battery (SIB) and Down Syndrome Mental Status Examination (DS-MSE). Biomarker distributions are described with strong statistical associations observed with participant age. The biomarker data contributes to understanding DS-AD across the spectrum of disease. Collectively, the biomarker data show evidence of DS-AD progression beginning at approximately 40 years of age. Exploring these data across the full LIFE-DSR longitudinal study population will be an important resource in understanding the onset, progression, and clinical profiles of DS-AD pathophysiology.
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Alcolea, Daniel, Eduard Vilaplana, Marc Suárez-Calvet, Ignacio Illán-Gala, Rafael Blesa, Jordi Clarimón, Albert Lladó et al. « CSF sAPPβ, YKL-40, and neurofilament light in frontotemporal lobar degeneration ». Neurology 89, no 2 (7 juin 2017) : 178–88. http://dx.doi.org/10.1212/wnl.0000000000004088.
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Objective:To analyze the clinical utility of 3 CSF biomarkers and their structural imaging correlates in a large cohort of patients with different dementia and parkinsonian syndromes within the spectrum of frontotemporal lobar degeneration (FTLD).Methods:We analyzed 3 CSF biomarkers (YKL-40, soluble β fragment of amyloid precursor protein [sAPPβ], neurofilament light [NfL]) and core Alzheimer disease (AD) biomarkers (β-amyloid1-42, total tau, phosphorylated tau) in patients with FTLD-related clinical syndromes (n = 159): behavioral variant of frontotemporal dementia (n = 68), nonfluent (n = 23) and semantic (n = 19) variants of primary progressive aphasia, progressive supranuclear palsy (n = 28), and corticobasal syndrome (n = 21). We also included patients with AD (n = 72) and cognitively normal controls (CN; n = 76). We compared cross-sectional biomarker levels between groups, studied their correlation with cortical thickness, and evaluated their potential diagnostic utility.Results:Patients with FTLD-related syndromes had lower levels of sAPPβ than CN and patients with AD. The levels of sAPPβ showed a strong correlation with cortical structural changes in frontal and cingulate areas. NfL and YKL-40 levels were high in both the FTLD and AD groups compared to controls. In the receiver operating characteristic analysis, the sAPPβ/YKL-40 and NfL/sAPPβ ratios had areas under the curve of 0.91 and 0.96, respectively, distinguishing patients with FTLD from CN, and of 0.84 and 0.85, distinguishing patients with FTLD from patients with AD.Conclusions:The combination of sAPPβ with YKL-40 and with NfL in CSF could be useful to increase the certainty of the diagnosis of FTLD-related syndromes in clinical practice.Classification of evidence:This study provides Class III evidence that CSF levels of sAPPβ, YKL-40, and NfL are useful to identify patients with FTLD-related syndromes.
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Gao, Yanpan, Yanyu Chen, Lun Wang, Chen Li et Wei Ge. « Serum-derived extracellular vesicles inhibit osteoclastogenesis in active-phase patients with SAPHO syndrome ». Therapeutic Advances in Musculoskeletal Disease 13 (janvier 2021) : 1759720X2110069. http://dx.doi.org/10.1177/1759720x211006966.
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Objective: Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is a rare chronic inflammatory disorder and the underlying pathogenesis is unclear. In this study, 88 SAPHO patients and 118 healthy controls were recruited to investigate the role of serum-derived extracellular vesicles (SEVs) in SAPHO syndrome. Methods: Quantitative proteomics was applied for SEVs proteome identification, and ELISA and Western blotting was performed to verify the results of mass spectrum data. In vitro osteoclastogenesis and osteogenesis assay was used to confirm the effects of SEVs on bone metabolism. Results: Tandem mass tagging-based quantitative proteomic analysis of SAPHO SEVs revealed differential expressed proteins involved in bone metabolism. Of these, serum amyloid A-1 (SAA1) and C-reactive protein (CRP) were upregulated. Higher SAA1 levels in SAPHO patients were confirmed by ELISA. In addition, SAA1 levels were positively correlated with CRP, an inflammatory marker related to the condition of patients. In vitro celluler studies confirmed that SAPHO SEVs inhibited osteoclastogenesis in patients mainly in the active phase of the disease. Further analysis demonstrated that Nucleolin was upregulated in osteoclasts of active-phase patients under SAPHO SEVs stimulation. Conclusion: In this study, we identified SAA1 as an additional inflammation marker that can potentially assist the diagnosis of SAPHO syndrome, and speculated that Nucleolin is a key regulator of osteoclastogenesis in active-phase patients.
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Koo, E. H., S. L. Squazzo, D. J. Selkoe et C. H. Koo. « Trafficking of cell-surface amyloid beta-protein precursor. I. Secretion, endocytosis and recycling as detected by labeled monoclonal antibody ». Journal of Cell Science 109, no 5 (1 mai 1996) : 991–98. http://dx.doi.org/10.1242/jcs.109.5.991.
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Amyloid beta-protein, the principal constituent of amyloid fibrils found in senile plaques and blood vessels in Alzheimer's disease, is constitutively produced and released into medium of cultured cells. Amyloid beta-protein is derived by proteolysis of the beta-amyloid precursor protein by unclear mechanisms. Beta-amyloid precursor protein is a transmembrane protein which can be processed to release a large secretory product or processed in the endosomal/lysosomal pathway without secretion. Previous studies have shown that from the cell surface, beta-amyloid precursor protein may be released after cleavage or internalized without cleavage, the latter in a pathway that both produces amyloid beta-protein and also targets some molecules to the lysosomal compartment. Analysis of beta-amyloid precursor protein trafficking is confounded by the concomitant secretion and internalization of molecules from the cell surface. To address this issue, we developed an assay, based on the binding of radioiodinated monoclonal antibody, to measure the release and internalization of cell surface beta-amyloid precursor protein in transfected cells. With this approach, we showed that surface beta-amyloid precursor protein is either rapidly released or internalized, such that the duration at the cell surface is very short. Approximately 30% of cell surface beta-amyloid precursor protein molecules are released. Following internalization, a fraction of molecules are recycled while the majority of molecules are rapidly sorted to the lysosomal compartment for degradation When the C terminus of beta-amyloid precursor protein is deleted, secretion is increased by approximately 2.5-fold as compared to wild-type molecules. There is concomitant decrease in internalization in these mutant molecules as well as prolongation of the resident time on the cell surface. This observation is consistent with recent evidence that signals within the cytoplasmic domain mediate beta-amyloid precursor protein internalization.
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INOUYE, Hideyo. « X-ray Diffraction Analysis of the .BETA.-Crystallite Assembly of Alzheimer .BETA.-Amyloid Protein Analogue. » Nihon Kessho Gakkaishi 35, no 5 (1993) : 347–51. http://dx.doi.org/10.5940/jcrsj.35.347.
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Nawrot, Barbara. « Targeting BACE with small inhibitory nucleic acids - a future for Alzheimer's disease therapy ? » Acta Biochimica Polonica 51, no 2 (30 juin 2004) : 431–44. http://dx.doi.org/10.18388/abp.2004_3582.
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beta-Secretase, a beta-site amyloid precursor protein (APP) cleaving enzyme (BACE), participates in the secretion of beta-amyloid peptides (Abeta), the major components of the toxic amyloid plaques found in the brains of patients with Alzheimer's disease (AD). According to the amyloid hypothesis, accumulation of Abeta is the primary influence driving AD pathogenesis. Lowering of Abeta secretion can be achieved by decreasing BACE activity rather than by down-regulation of the APP substrate protein. Therefore, beta-secretase is a primary target for anti-amyloid therapeutic drug design. Several approaches have been undertaken to find an effective inhibitor of human beta-secretase activity, mostly in the field of peptidomimetic, non-cleavable substrate analogues. This review describes strategies targeting BACE mRNA recognition and its down-regulation based on the antisense action of small inhibitory nucleic acids (siNAs). These include antisense oligonucleotides, catalytic nucleic acids - ribozymes and deoxyribozymes - as well as small interfering RNAs (siRNAs). While antisense oligonucleotides were first used to identify an aspartyl protease with beta-secretase activity, all the strategies now demonstrate that siNAs are able to inhibit BACE gene expression in a sequence-specific manner, measured both at the level of its mRNA and at the level of protein. Moreover, knock-down of BACE reduces the intra- and extracellular population of Abeta40 and Abeta42 peptides. An anti-amyloid effect of siNAs is observed in a wide spectrum of cell lines as well as in primary cortical neurons. Thus targeting BACE with small inhibitory nucleic acids may be beneficial for the treatment of Alzheimer's disease and for future drug design.
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Deleidi, Michela, et Walter Maetzler. « Protein Clearance Mechanisms of Alpha-Synuclein and Amyloid-Beta in Lewy Body Disorders ». International Journal of Alzheimer's Disease 2012 (2012) : 1–9. http://dx.doi.org/10.1155/2012/391438.
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Protein clearance is critical for the maintenance of the integrity of neuronal cells, and there is accumulating evidence that in most—if not all—neurodegenerative disorders, impaired protein clearance fundamentally contributes to functional and structural alterations eventually leading to clinical symptoms. Dysfunction of protein clearance leads to intra- and extraneuronal accumulation of misfolded proteins and aggregates. The pathological hallmark of Lewy body disorders (LBDs) is the abnormal accumulation of misfolded proteins such as alpha-synuclein (Asyn) and amyloid-beta (Abeta) in a specific subset of neurons, which in turn has been related to deficits in protein clearance. In this paper we will highlight common intraneuronal (including autophagy and unfolded protein stress response) and extraneuronal (including interaction of neurons with astrocytes and microglia, phagocytic clearance, autoimmunity, cerebrospinal fluid transport, and transport across the blood-brain barrier) protein clearance mechanisms, which may be altered across the spectrum of LBDs. A better understanding of the pathways underlying protein clearance—in particular of Asyn and Abeta—in LBDs may result in the identification of novel biomarkers for disease onset and progression and of new therapeutic targets.
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D'Souza, Anita, Kathryn E. Flynn, Binod Dhakal, Saurabh Chhabra, Marcelo C. Pasquini et Parameswaran Hari. « Adjuvant Doxycycline to Enhance Anti-Amyloid Effects : Results from the DUAL (Doxycycline to Upgrade response in AL amyloidosis) Study ». Blood 132, Supplement 1 (29 novembre 2018) : 1999. http://dx.doi.org/10.1182/blood-2018-99-114783.
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Abstract Background: Light chain (AL) amyloidosis is associated with misfolded, insoluble fibril deposits in vital organs such as the heart, kidneys, liver, and nerves, derived from immunoglobulin light chains made by clonal plasma cells. Plasma cell-directed, standard-of-care chemotherapy has no effect on pre-formed fibrils. Hematologic response is thus insufficient for organ amyloid responses and organ improvement can lag hematologic response by months to years. Fibril-directed therapies are critical to improve early mortality of AL. Doxycycline has been reported to produce fibril disruption, reduce AL deposits and control light chain toxicity. It has been studied in localized AL amyloidosis and other amyloid subtypes. We conducted a phase 2 trial of doxycycline for use in conjunction with chemotherapy in AL. Herein, we report the outcomes of systemic AL patients treated on this study. Patients and Methods: This was an open label, single center, phase 2 pilot trial listed under clinicaltrials.gov (NCT02207556). The study was opened between 12/2014 - 06/2017. The last patient completed end-of-study assessment in 07/2018. Based on predominant symptoms and organ involvement, each patient was labeled to have 1 target amyloid organ involved. Patients were treated with oral doxycycline 100 mg twice daily in conjunction with chemotherapy per physician discretion. Patients were staged using the 2012 staging system. Hematologic and organ responses were categorized based on the consensus guidelines for conduct and reporting of clinical trials in AL amyloidosis published in 2012 for cardiac, renal and hepatic organ involvement and by radiologic measures for soft tissue involvement. The objectives were to study early mortality at 1, 3, 6, and 12 months after enrollment, target amyloid organ response rates at 6 and 12 months, and quality of life (QoL) using the PROMIS Global Health Index at 3-monthly intervals during the study. Results: Of 31 patients enrolled on this study, 25 had systemic AL (6 patients with localized AL syndromes will be described separately). The median age at diagnosis was 61.3 years (range 38.3-77.3), 64% were male, 2012 stage was I in 3 (12%), II in 9 (36%), III in 6 (24%) and IV in 7 (28%). The amyloid clone was lambda in 17 (68%). The median baseline values with range were: hemoglobin 12.3 (9.7-16.5) g/dL, albumin 3.7 (1.1-4.8) g/dL, creatinine 1.07 (0.6-2.42) mg/dL, 24-hour urine protein 0.97 (0.15-16.7) g/day and alkaline phosphatase 77 (42-597) IU/L. The median difference in involved and uninvolved free light chains was 258.6 (26-978.4) mg/L, NT-proBNP was 2564 (65-18333) pg/mL and troponin T was 0.017 (<0.011-0.342) ng/mL. Among AL organ involvement, 16% had 1, 24% had 2, 16% had 3, and 44% had >3 organs involved with amyloid, with 60% cardiac, 72% renal, 24% hepatic, 36% soft tissue, 28% gastrointestinal, 20% autonomic nervous system, and 8% peripheral nerve AL involvement. The median follow-up was 21.4 (12.2-40.3) months. All patients received concurrent CyBorD chemotherapy. Early mortality was 0 at 1 month, 2 (8%) at 3 months, 3 (12%) at 6 months and 5 (20%) at 1 year. Target organ involvement and responses at 6 and 12 months are shown in the table. In an intent-to-treat analysis of organ responses, at 6 months 24% had response, 32% had stable disease and 44% had progression (including 3 deaths prior to 6 months). At 12 months, 36% had target organ response, 32% had stable disease and 36% had progression (including 5 deaths). QoL showed improvement in both physical and mental domains at the end of treatment (figure). Overall hematologic response among survivors was 100% at 1-year including 40% complete, 45% very good, and 15% partial responses. The most common adverse event was skin rash and photosensitivity. One patient with end-stage heart failure and multiple hospitalizations, developed Clostridium difficile diarrhea while hospitalized, during the study period. Fifteen patients (60%) underwent melphalan-based autologous stem cell transplantation- 14 within 1 year after diagnosis, and in 1 delayed until relapsed disease 2 years after diagnosis. The 100-day mortality among transplanted patients was 0. Conclusions: In newly diagnosed systemic AL amyloidosis, doxycycline was safe with concurrent chemotherapy. The low 1-year early mortality of 20% and autologous stem cell transplant rate of 60% compares favorably to prior reports. These findings warrant a randomized, multicenter study. Disclosures D'Souza: Prothena: Consultancy, Research Funding; Merck: Research Funding; Takeda: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Dhakal:Celgene: Consultancy, Honoraria; Takeda: Honoraria, Research Funding; Amgen: Honoraria. Hari:Janssen: Honoraria; Amgen Inc.: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding.
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Inouye, H., P. E. Fraser et D. A. Kirschner. « Structure of beta-crystallite assemblies formed by Alzheimer beta-amyloid protein analogues : analysis by x-ray diffraction ». Biophysical Journal 64, no 2 (février 1993) : 502–19. http://dx.doi.org/10.1016/s0006-3495(93)81393-6.
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Sakalauskas, Andrius, Mantas Ziaunys, Ruta Snieckute et Vytautas Smirnovas. « Autoxidation Enhances Anti-Amyloid Potential of Flavone Derivatives ». Antioxidants 10, no 9 (7 septembre 2021) : 1428. http://dx.doi.org/10.3390/antiox10091428.
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The increasing prevalence of amyloid-related disorders, such as Alzheimer’s or Parkinson’s disease, raises the need for effective anti-amyloid drugs. It has been shown on numerous occasions that flavones, a group of naturally occurring anti-oxidants, can impact the aggregation process of several amyloidogenic proteins and peptides, including amyloid-beta. Due to flavone autoxidation at neutral pH, it is uncertain if the effective inhibitor is the initial molecule or a product of this reaction, as many anti-amyloid assays attempt to mimic physiological conditions. In this work, we examine the aggregation-inhibiting properties of flavones before and after they are oxidized. The oxidation of flavones was monitored by measuring the UV-vis absorbance spectrum change over time. The protein aggregation kinetics were followed by measuring the amyloidophilic dye thioflavin-T (ThT) fluorescence intensity change. Atomic force microscopy was employed to image the aggregates formed with the most prominent inhibitors. We demonstrate that flavones, which undergo autoxidation, have a far greater potency at inhibiting the aggregation of both the disease-related amyloid-beta, as well as a model amyloidogenic protein—insulin. Oxidized 6,2′,3′-trihydroxyflavone was the most potent inhibitor affecting both insulin (7-fold inhibition) and amyloid-beta (2-fold inhibition). We also show that this tendency to autoxidize is related to the positions of the flavone hydroxyl groups.
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Uéda, K., H. Fukushima, E. Masliah, Y. Xia, A. Iwai, M. Yoshimoto, D. A. Otero, J. Kondo, Y. Ihara et T. Saitoh. « Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease ». Proceedings of the National Academy of Sciences 90, no 23 (1 décembre 1993) : 11282–86. http://dx.doi.org/10.1073/pnas.90.23.11282.
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A neuropathological hallmark of Alzheimer disease (AD) is a widespread amyloid deposition. We analyzed the entire amino acid sequences in an amyloid preparation and found, in addition to the major beta/A4-protein (A beta) fragment, two unknown peptides. We raised antibodies against synthetic peptides using subsequences of these peptides. These antibodies immunostained amyloid in neuritic and diffuse plaques as well as vascular amyloid. Electron microscopic analysis demonstrated that the immunostaining was localized on amyloid fibrils. We have isolated an apparently full-length cDNA encoding a 140-amino-acid protein within which two previously unreported amyloid sequences are encoded in tandem in the most hydrophobic domain. We tentatively named this 35-amino acid peptide NAC (non-A beta component of AD amyloid) and its precursor NACP. NAC is the second component, after A beta, identified chemically in the purified AD amyloid preparation. Secondary structure predictions indicate that the NAC peptide sequence has a strong tendency to form beta-structures consistent with its association with amyloid. NACP is detected as a M(r) 19,000 protein in the cytosolic fraction of brain homogenates and comigrates on immunoblots with NACP synthesized in Escherichia coli from NACP cDNA. NACP mRNA is expressed principally in brain but is also expressed in low concentrations in all tissues examined except in liver, suggesting its ubiquitous and brain-specific functions. The availability of the cDNA encoding full-length NACP should help to elucidate the mechanisms of amyloidosis in AD.
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Gerasimova, Elizaveta M., Sergey A. Fedotov, Daniel V. Kachkin, Elena S. Vashukova, Andrey S. Glotov, Yury O. Chernoff et Aleksandr A. Rubel. « Protein Misfolding during Pregnancy : New Approaches to Preeclampsia Diagnostics ». International Journal of Molecular Sciences 20, no 24 (7 décembre 2019) : 6183. http://dx.doi.org/10.3390/ijms20246183.
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Preeclampsia (PE) is a multisystem heterogeneous complication of pregnancy remaining a leading cause of maternal and perinatal morbidity and mortality over the world. PE has a large spectrum of clinical features and symptoms, which make diagnosis challenging. Despite a long period of studying, PE etiology is still unclear and there are no reliable rapid tests for early diagnosis of this disease. During the last decade, it was shown that proteins misfolding and aggregation are associated with PE. Several proteins, including amyloid beta peptide, transthyretin, alpha-1 antitrypsin, albumin, IgG k-free light chains, and ceruloplasmin are dysregulated in PE, resulting in toxic deposition of amyloid-like aggregates in the placenta and body fluids. It is also possible that aggregated proteins induce defective trophoblast invasion, placental ischemia, ER stress, and promote PE manifestation. The fact that protein aggregation is an emerging biomarker of PE provides an opportunity to develop new diagnostic approaches based on amyloids special features, such as Congo red (CR) staining and thioflavin T (ThT) enhanced fluorescence.
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Alabed, Sedra, Heping Zhou, Ilker K. Sariyer et Sulie L. Chang. « Meta-Analysis of Methamphetamine Modulation on Amyloid Precursor Protein through HMGB1 in Alzheimer’s Disease ». International Journal of Molecular Sciences 22, no 9 (30 avril 2021) : 4781. http://dx.doi.org/10.3390/ijms22094781.
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The deposition of amyloid-beta (Aβ) through the cleavage of amyloid-beta precursor protein (APP) is a biomarker of Alzheimer’s disease (AD). This study used QIAGEN Ingenuity Pathway Analysis (IPA) to conduct meta-analysis on the molecular mechanisms by which methamphetamine (METH) impacts AD through modulating the expression of APP. All the molecules affected by METH and APP were collected from the QIAGEN Knowledge Base (QKB); 78 overlapping molecules were identified. Upon simulation of METH exposure using the “Molecule Activity Predictor” feature, eight molecules were found to be affected by METH and exhibited activation relationships on APP expression at a confidence of p = 0.000453 (Z-score = 3.51, two-tailed). Core Analysis of these eight molecules identified High Mobility Group Box protein 1 (HMGB1) signaling pathway among the top 5 canonical pathways with most overlap with the 8-molecule dataset. Simulated METH exposure increased APP expression through HMGB1 at a confidence of p < 0.00001 (Z-score = 7.64, two-tailed). HMGB1 is a pathogenic hallmark in AD progression. It not only increases the production of inflammatory mediators, but also mediates the disruption of the blood-brain barrier. Our analyses suggest the involvement of HMGB1 signaling pathway in METH-induced modulation of APP as a potential casual factor of AD.
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Akbor, Maruf Mohammad, Nobuyuki Kurosawa, Hiroki Nakayama, Ayumi Nakatani, Koji Tomobe, Yoichi Chiba, Masaki Ueno, Masashi Tanaka, Yasuyuki Nomura et Masaharu Isobe. « Polymorphic SERPINA3 prolongs oligomeric state of amyloid beta ». PLOS ONE 16, no 3 (4 mars 2021) : e0248027. http://dx.doi.org/10.1371/journal.pone.0248027.
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Molecular chaperon SERPINA3 colocalizes with accumulated amyloid peptide in Alzheimer’s disease (AD) patient’s brain. From the QTL analysis, we narrowed down Serpina3 with two SNPs in senescence-accelerated mouse prone (SAMP) 8 strain. Our study showed SAMP8 type Serpina3 prolonged retention of oligomeric Aβ 42 for longer duration (72 hr) while observing under transmission electron microscope (TEM). From Western blot results, we confirmed presence of Aβ 42 oligomeric forms (trimers, tetramers) were maintained for longer duration only in the presences of SAMP8 type Serpina3. Using SH-SY5Y neuroblastoma cell line, we observed until 36 hr preincubated Aβ 42 with SAMP8 type Serpina3 caused neuronal cell death compared to 12 hr preincubated Aβ 42 with SAMR1 or JF1 type Serpina3 proteins. Similar results were found by extending this study to analyze the effect of polymorphism of SERPINA3 gene of the Japanese SNP database for geriatric research (JG-SNP). We observed that polymorphic SERPINA3 I308T (rs142398813) prolonged toxic oligomeric Aβ 42 forms till 48 hr in comparison to the presence wild type SERPINA3 protein, resulting neuronal cell death. From this study, we first clarified pathogenic regulatory role of polymorphic SERPINA3 in neurodegeneration.
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Brancaccio, D., G. M. Ghiggeri, P. Braidotti, A. Garberi, M. Gallieni, V. Bellotti, U. Zoni, R. Gusmano et G. Coggi. « Deposition of kappa and lambda light chains in amyloid filaments of dialysis-related amyloidosis. » Journal of the American Society of Nephrology 6, no 4 (octobre 1995) : 1262–70. http://dx.doi.org/10.1681/asn.v641262.
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beta 2-Microglobulin (beta 2m) is considered to be the amyloidogenic precursor in dialysis-related amyloidosis, although the implication of other relevant cofactors in the pathogenesis of this disease has also been hypothesized. It is conceivable that substances found in amyloid deposits might represent something more than simple codeposition, possibly playing a pathogenic role in amyloidogenesis. Along these lines, a detailed analysis of the protein composition of amyloid fibrils purified from synovial material surgically obtained from nine patients on long-term dialysis was carried out. By the use of sodium dodecyl sulfate-polyacrylamide gel electrophoresis, several other protein components, in addition to beta 2m, were found. These were characterized by NH2 amino-terminal sequencing and immunoblotting. In fibrils obtained by water extraction, which fulfill the electron microscopy criteria of highly pure amyloid material, polyclonal kappa and lambda light chains were detected with a concentration of 15 micrograms/mL in the water extraction material; the beta 2m concentration was 200 micrograms/mL. Light microscopy immunohistochemistry was performed on samples from five patients. Amyloid deposits reacted with anti-beta 2m, and anti-light (kappa, lambda), chain antibodies. The immunoreaction of amyloid filaments to anti-beta 2m, anti-lambda, and anti-kappa light chain antibodies was also tested by electron microscopy by use of the immunogold staining procedure. Amyloid filaments were labeled by the three antibodies and showed a different intensity of immunostaining apparently related to their different aggregation pattern. These observations demonstrate that polyclonal immunoglobulin light chains (kappa and lambda) are not contaminants but, together with beta 2m, represent a major constituent of amyloid deposits in dialysis-related osteoarticular amyloidosis, thus indicating their possible role in amyloidogenesis.
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Liu, Guitao, Yingjia Liu, Lu Jin, Cuidong Li, Liping Nie, Yanhua Wei, Wenyu Wang et al. « Effect of Xinjiang UyghurVernonia anthelminticaWilld Injection Treatment with Silicosis Fibrosis ». BioMed Research International 2016 (2016) : 1–11. http://dx.doi.org/10.1155/2016/5139651.
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Objective. To observe the curative effect of VAWI on Xinjiang Uygur patients with silicosis fibrosis.Methods. After we diagnosed the 40 patients with the first phase of silicosis, we randomly divided them into two groups: the basic treatment group (group A,n=20) and the VAWI group (group B,n=20). At the same time, we selected the age-matched healthy patients (n=20). We applied the combined protein chip with SELDI-TOF-MS to carry out the serum analysis. The data were analyzed throughout data preprocessing, difference in PEAK screening, hierarchical cluster analysis, and Principal Component Analysis (PCA). We built decision tree model and predict the difference between the PEAK corresponding proteins.Results. The proteins peaks corresponding to name, predicted protein, and gene name were as follows: M2001_69, amyloid beta a4 protein, APP, and M2017_02, amyloid beta a4 protein, APP. The different expression of proteins in patients with silicosis was found before and after with VAWI treatment. The predicted proteins were as follows: M1982_50, amyloid beta a4 protein, APP; M3164_50, fibrinogen alpha chain frag, FGA; M3379_28, fibrinogen alpha chain frag, FGA; and so on.Conclusion. VAWI presented curative effect on patients with silicosis fibrosis via the alternation of proteins expression in serum.
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Seckinger, Anja, Ute Hegenbart, Susanne Beck, Martina Emde, Tilmann Bochtler, Christoph Kimmich, Carsten Müller-Tidow, Anna Jauch, Stefan Schönland et Dirk Hose. « AL Amyloidosis — Pathogenesis and Prognosis Are Determined By the Amyloidogenic Potential of the Light Chain and the Molecular Characteristics of Malignant Plasma Cells ». Blood 132, Supplement 1 (29 novembre 2018) : 187. http://dx.doi.org/10.1182/blood-2018-187.
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Abstract INTRODUCTION. Systemic light chain amyloidosis (AL) is caused by accumulation of plasma cells producing misfolded monoclonal light chains depositing as amyloid fibrils in different organs, most frequently heart and kidney. AIM of our study is first assessing the molecular characteristics of malignant plasma cells from AL-patients in relation to those from MGUS, asymptomatic, and symptomatic myeloma: Are these plasma cells different, does this difference explain amyloidogenicity? Does AL correspond to a certain developmental stage during evolution of symptomatic myeloma? Secondly, to what extent is prognosis determined by amyloid-deposition (organotropism, amount, amyloidogenicity) vs. number and molecular characteristics of malignant plasma cells? PATIENTS & METHODS . Consecutive patients (n=3023) with AL (n=582), MGUS (n=306), asymptomatic (n=444, AMM), or previously untreated, therapy-requiring multiple myeloma (n=1691, MM) were included. CD138-purified plasma cell samples were subjected to iFISH (n=582/306/444/1691), 1297 to gene expression profiling using Affymetrix U133 2.0 plus arrays (n=196/64/272/765), 712 to RNA- (n=124/52/38/489), and 258 to whole exome sequencing (n=115/53/39/51). Samples of normal bone marrow plasma cells, memory B-cells, and polyclonal plasmablasts were used as comparators. The CoMMpass-cohort (n=647) was used as comparator for the mutational spectrum of myeloma. RESULTS . Prognosis. By AL-factors. Expectedly, organ involvement, i.e. heart only vs. kidney only vs. heart+kidney vs. other (overall survival (OS), P=.001), the amount of free light chains (dFLC ≥18 mg/dL, HR=2.56, P=.01), and the cardiac European Mayo IIIB score (I/II/IIIA/IIIB, median OS 110/55/16/3 months, HR=1/1.94/3.73/7.90, P<.001) strongly determine prognosis (Fig. 1A). By malignant plasma cell factors. High proliferation rate (HR=3.58, P=.001) and expression-based risk factors for MM (GEP70 high, HR=2.38, P=.005; Rs-score high HR=4.63, P<.001) identify patients with very adverse prognosis (Fig. 1A). Tumor load, e.g. plasma cell infiltration >10%/>30% (HR=1.31/1.81, P=.01, P=.002) and M-protein ≥ 30g/l (HR=3.01, P=.005), are likewise prognostic (Fig. 1A). In multivariate analysis, all tested AL-specific (European Mayo IIIB score) and malignant plasma cell factors (proliferation or GEP70 and plasma cell infiltration) are independent. Molecular characteristics.iFISH. As MM (96.2%) and AMM (92.8%) AL-patients (93.1%) carry at least one recurrent myeloma typical aberration. The mean number of progression-associated aberrations in AL (n=0.98) fits between MGUS (n=0.85) and AMM (n=1.45) with significant difference compared to AMM (P<.001) unlike to MGUS. Main differences in frequency are found for t(11;14) and hyperdiploidy with a comparable pattern of non-etiologic aberrations. Gene expression (GEP and RNA-seq). Aberrant plasma cells in AL amyloidosis show the least difference with AMM, followed by MGUS and MM. In principal component analysis, AL overlaps with AMM and MGUS, independent of presence or absence of heart involvement (Fig. 1B). Pairwise assessment of similarity using a multivariate generalization of the squared Pearson correlation coefficient shows closest similarity to AMM and MM followed by MGUS, with comparable differences to normal plasma cells, polyclonal plasmablasts, and memory B-cells. Significantly more AL-patients present with higher proliferation rate vs MGUS (P<.001) and AMM (P<.02). AL and MM differ significantly regarding distinct molecular entities as determined by GEP (e.g. TC-classification; Fig. 1C). Mutation spectrum in AL amyloidosis vs. MM. From the 20 most frequently synonymously mutated non-Ig transcripts (CoMMpass-cohort), 16 could likewise be detected in AL amyloidosis, i.e. KRAS, NRAS, IGLL5, DIS3, FAM46C, MUC16, BRAF, TRAF3, PCLO, RYR2, FATA4, CSMD3, TP53, DNAH5, RYR2A, and FLG. CCND1 mutations were significantly more frequent in AL and AMM compared to MM (P=.02). DISCUSSION & CONCLUSION. Pathogenesis and prognosis of AL amyloidosis are explained both by AL-specific and malignant plasma cell characteristics. Aberrant plasma cells in AL amyloidosis show the same aberration- and expression pattern and a "molecular age" between MGUS and AMM, most closely resembling the latter. AL amyloidosis is thus mostly a rather early plasma cell dyscrasia with an unstable and toxic immunoglobulin light chain. Disclosures Seckinger: Celgene: Research Funding; EngMab: Research Funding; Sanofi: Research Funding. Hose:Celgene: Honoraria, Research Funding; Sanofi: Research Funding; EngMab: Research Funding.
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Liu, Sijun, Yuying Zhao, Xiaoying Su, Chengcheng Zhou, Peifen Yang, Qiusan Lin, Shijun Li et al. « Reconstruction of Alzheimer’s Disease Cell Model In Vitro via Extracted Peripheral Blood Molecular Cells from a Sporadic Patient ». Stem Cells International 2020 (18 décembre 2020) : 1–10. http://dx.doi.org/10.1155/2020/8897494.
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The establishment of human-induced pluripotent stem cell (iPSC) models from sporadic Alzheimer’s disease (sAD) patients is necessary and could potentially benefit research into disease etiology and therapeutic strategies. However, the development of sAD iPSC models is still limited due to the multifactorial nature of the disease. Here, we extracted peripheral blood mononuclear cells (PBMCs) from a patient with sAD and induced them into iPSC by introducing the Sendai virus expressing Oct3/4, Sox2, c-Myc, and Klf4, which were subsequently induced into neural cells to build the cell model of AD. Using alkaline phosphatase staining, immunofluorescence staining, karyotype analysis, reverse transcription-polymerase chain reaction (RT-PCR), and teratoma formation in vitro, we demonstrated that the iPSC derived from PMBCs (PBMC-iPSC) had a normal karyotype and potential to differentiate into three embryonic layers. Immunofluorescence staining and quantitative real-time polymerase chain reaction (qPCR) suggested that PBMC-iPSCs were successfully differentiated into neural cells. Detection of beta-amyloid protein oligomer (AβO), beta-amyloid protein 1-40 (Aβ 1-40), and beta-amyloid protein 1-42 (Aβ 1-42) indicated that the AD cell model was satisfactorily constructed in vitro. In conclusion, this study has successfully generated an AD cell model with pathological features of beta-amyloid peptide deposition using PBMC from a patient with sAD.
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Caporaso, GL, K. Takei, SE Gandy, M. Matteoli, O. Mundigl, P. Greengard et P. De Camilli. « Morphologic and biochemical analysis of the intracellular trafficking of the Alzheimer beta/A4 amyloid precursor protein ». Journal of Neuroscience 14, no 5 (1 mai 1994) : 3122–38. http://dx.doi.org/10.1523/jneurosci.14-05-03122.1994.
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Tanaka, Seigo, Akiko Okuda et Masanori Takehashi. « P2-274 : Microarray analysis of gene expression profile in astrocytes after exposure to amyloid beta protein ». Alzheimer's & ; Dementia 7 (juillet 2011) : S399—S400. http://dx.doi.org/10.1016/j.jalz.2011.05.1153.
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Stepanenko, Olga V., Maksim I. Sulatsky, Ekaterina V. Mikhailova, Olesya V. Stepanenko, Irina M. Kuznetsova, Konstantin K. Turoverov et Anna I. Sulatskaya. « Trypsin Induced Degradation of Amyloid Fibrils ». International Journal of Molecular Sciences 22, no 9 (2 mai 2021) : 4828. http://dx.doi.org/10.3390/ijms22094828.
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Proteolytic enzymes are known to be involved in the formation and degradation of various monomeric proteins, but the effect of proteases on the ordered protein aggregates, amyloid fibrils, which are considered to be extremely stable, remains poorly understood. In this work we study resistance to proteolytic degradation of lysozyme amyloid fibrils with two different types of morphology and beta-2-microglobulun amyloids. We showed that the proteolytic enzyme of the pancreas, trypsin, induced degradation of amyloid fibrils, and the mechanism of this process was qualitatively the same for all investigated amyloids. At the same time, we found a dependence of efficiency and rate of fibril degradation on the structure of the amyloid-forming protein as well as on the morphology and clustering of amyloid fibrils. It was assumed that the discovered relationship between fibrils structure and the efficiency of their degradation by trypsin can become the basis of a new express method for the analysis of amyloids polymorphism. Unexpectedly lower resistance of both types of lysozyme amyloids to trypsin exposure compared to the native monomeric protein (which is not susceptible to hydrolysis) was attributed to the higher availability of cleavage sites in studied fibrils. Another intriguing result of the work is that the cytotoxicity of amyloids treated with trypsin was not only failing to decline, but even increasing in the case of beta-2-microglobulin fibrils.
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Beach, C. M., M. C. De Beer, J. D. Sipe, L. D. Loose et F. C. De Beer. « Human serum amyloid A protein. Complete amino acid sequence of a new variant ». Biochemical Journal 282, no 2 (1 mars 1992) : 615–20. http://dx.doi.org/10.1042/bj2820615.
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Serum amyloid A protein (SAA), an acute-phase reactant and apolipoprotein of high-density lipoprotein, is a polymorphic protein with six reported isoforms. These are the products of three genes, i.e., cDNA pA1, cDNA pSAA82 and genomic DNA SAAg9, the last two being allelic variants at a single locus. We have identified an individual with additional novel SAA isoforms on isoelectric-focusing analysis. By using 3-bromo-3-methyl-2-(2′-nitrophenylsulphenyl)-indolenine (BNPS-skatole) cleavage of the protein at tryptophan residues we obtained the complete amino acid sequence of a novel isoform. Additional cleavage by endoproteinase Asp-N allowed verification of the tryptophan residues and complete amino acid sequence of both isoforms. The suitability of this approach to the rapid sequencing of SAA was demonstrated. Sequence analysis and quantification suggest that these isoforms are the result of the first confirmed allelic variation at the SAA1 locus. We designate the protein products of this allele SAA1 beta (pI 6.1) and SAA1 beta des-Arg (pI 5.6).
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Urano, Yasuomi, Mina Takahachi, Ryo Higashiura, Hitomi Fujiwara, Satoru Funamoto, So Imai, Eugene Futai, Michiaki Okuda, Hachiro Sugimoto et Noriko Noguchi. « Curcumin Derivative GT863 Inhibits Amyloid-Beta Production via Inhibition of Protein N-Glycosylation ». Cells 9, no 2 (3 février 2020) : 349. http://dx.doi.org/10.3390/cells9020349.
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Amyloid-β (Aβ) peptides play a crucial role in the pathogenesis of Alzheimer’s disease (AD). Aβ production, aggregation, and clearance are thought to be important therapeutic targets for AD. Curcumin has been known to have an anti-amyloidogenic effect on AD. In the present study, we performed screening analysis using a curcumin derivative library with the aim of finding derivatives effective in suppressing Aβ production with improved bioavailability of curcumin using CHO cells that stably express human amyloid-β precursor protein and using human neuroblastoma SH-SY5Y cells. We found that the curcumin derivative GT863/PE859, which has been shown to have an inhibitory effect on Aβ and tau aggregation in vivo, was more effective than curcumin itself in reducing Aβ secretion. We further found that GT863 inhibited neither β- nor γ-secretase activity, but did suppress γ-secretase-mediated cleavage in a substrate-dependent manner. We further found that GT863 suppressed N-linked glycosylation, including that of the γ-secretase subunit nicastrin. We also found that mannosidase inhibitors that block the mannose trimming step of N-glycosylation suppressed Aβ production in a similar fashion, as was observed as a result of treatment with GT863. Collectively, these results suggest that GT863 downregulates N-glycosylation, resulting in suppression of Aβ production without affecting secretase activity.
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Kaarsholm, N. C., A. M. Kolstrup, S. E. Danielsen, J. Holm et S. I. Hansen. « Ligand-induced conformation change in folate-binding protein ». Biochemical Journal 292, no 3 (15 juin 1993) : 921–25. http://dx.doi.org/10.1042/bj2920921.
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C.d. and fluorescence spectroscopy have been used to investigate the effect of ligand binding on the structure and stability of folate-binding protein (FBP) from cow's whey. The c.d. spectrum of unligated FBP predicts the following secondary structure: 22% helix, 25% antiparallel beta-strand, 5% parallel beta-strand, 17% turn and 31% random-coil structure. Folate binding to FBP results in significant changes in the c.d. spectrum. Analysis of the spectrum shows a 10% decrease in antiparallel beta-strand as a result of ligand binding. Folate binding also leads to strong quenching of FBP tryptophan fluorescence. The magnitude of the quench is proportional to ligand binding. The guanidinium chloride-induced unfolding of FBP is shown to be a multistate process. Detection by c.d. and fluorescence spectroscopy lead to non-identical transitions. Modelling studies are consistent with the existence of a stable folding intermediate. Ligand binding to FBP increases the apparent folding stability of the molecule. Simultaneous detection by c.d. and fluorescence indicate that the apparent increased folding stability is derived from ligand-induced aggregation of FBP.
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Besli, Nail, et Guven Yenmis. « Assessment of the Interaction of Aggregatin Protein with Amyloid-Beta (Aβ) at the Molecular Level via In Silico Analysis ». Acta Chimica Slovenica 67, no 4 (15 décembre 2020) : 1262–72. http://dx.doi.org/10.17344/acsi.2020.6175.
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Alzheimer’s disease is a major neurodegenerative illness whose prevalence is increasing worldwide but the molecular mechanism remains unclear. There is some scientific evidence that the molecular complexity of Alzheimer’s pathophysiology is associated with the formation of extracellular amyloid-beta plaques in the brain. A novel cross- phenotype association analysis of imaging genetics reported a brain atrophy susceptibility gene, namely FAM222A and the protein Aggregatin encoded by FAM222A interacts with amyloid-beta (Aβ)-peptide (1-42) through its N-terminal Aβ binding domain and facilitates Aβ aggregation. The function of Aggregatin protein is unknown, and its three-dimensional structure has not been analyzed experimentally yet. Our goal was to investigate the interaction of Aggregatin with Aβ in detail by in silico analysis, including the 3D structure prediction analysis of Aggregatin protein by homology modeling. Our analysis verified the interaction of the C-terminal domain of model protein with the N-terminal domain of Aβ. This is the first attempt to demonstrate the interaction of Aggregatin with the Aβ. These results confirmed in vitro and in vivo study reports claiming FAM222A helping to ease the aggregating of the Aβ-peptide.
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Yoshikawa, Tomoki, Ziyang Zhang, Kaoru Yamashita et Minoru Noda. « Biosensing of Interaction between Liposome of Model Cell Membrane and Amyloid-Beta Protein by Dielectric Dispersion Analysis ». Procedia Engineering 120 (2015) : 560–63. http://dx.doi.org/10.1016/j.proeng.2015.08.723.
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Lou, Yuxuan, Shiyuan Sun et Jiangqi Tan. « Pathogenesis of Alzheimer’s disease and its treatments : A systematic review ». E3S Web of Conferences 308 (2021) : 02012. http://dx.doi.org/10.1051/e3sconf/202130802012.
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Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by loss of memory and cognition. In this review article, three main pathogenesis of AD were described: Amyloid-beta hypothesis, Tau protein hyperphosphorylation and Neurotransmitter decrease hypothesis. Specifically, amyloid-beta accumulation can be detrimental for nervous system for Amyloid-beta hypothesis, while Tau protein hyperphosphorylation can cause the breakdown of nerve cells. With regard to Neurotransmitter decrease hypothesis, it is deemed as the direct reason to cause Alzheimer’s disease. On top of that, mainstream treatments therapy and their features, advantages and disadvantages are discussed. Firstly, medicine treatments corresponding to its pathogenesis are introduced. Secondly, gene therapy is also demonstrated which alleviates Alzheimer’s disease be means of gene modification, inactivation and immune regulation. Finally, the stem cells therapy is also described as well as other therapies. Based on our analysis, combined therapy should be put into practice to achieve a better effect. Moreover, more knowledge about AD pathogenesis is required for researchers, which provides theoretical basis and reference for treatments. These results shed light for future research of AD.
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Sparacia, Gianvincenzo, Francesco Agnello, Giuseppe La Tona, Alberto Iaia, Federico Midiri et Benedetta Sparacia. « Assessment of cerebral microbleeds by susceptibility-weighted imaging in Alzheimer’s disease patients : A neuroimaging biomarker of the disease ». Neuroradiology Journal 30, no 4 (2 mai 2017) : 330–35. http://dx.doi.org/10.1177/1971400916689483.
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Purpose The objective of this study was to correlate the presence and distribution of cerebral microbleeds in Alzheimer’s disease patients with cerebrospinal fluid biomarkers (amyloid-beta and phosphorylated tau 181 protein levels) and cognitive decline by using susceptibility-weighted imaging magnetic resonance sequences at 1.5 T. Material and methods Fifty-four consecutive Alzheimer’s disease patients underwent brain magnetic resonance imaging at 1.5 T to assess the presence and distribution of cerebral microbleeds on susceptibility-weighted imaging images. The images were analyzed in consensus by two neuroradiologists, each with at least 10 years’ experience. Dementia severity was assessed with the Mini-Mental State Examination score. A multiple regression analysis was performed to assess the associations between the number and location of cerebral microbleed lesions with the age, sex, duration of the disease, cerebrospinal fluid amyloid-beta and phosphorylated tau 181 protein levels, and cognitive functions. Results A total of 296 microbleeds were observed in 54 patients; 38 patients (70.4%) had lobar distribution, 13 patients (24.1%) had non-lobar distribution, and the remaining three patients (5.6%) had mixed distribution, demonstrating that Alzheimer’s disease patients present mainly a lobar distribution of cerebral microbleeds. The age and the duration of the disease were correlated with the number of lobar cerebral microbleeds ( P < 0.001). Cerebrospinal fluid amyloid-beta, phosphorylated tau 181 protein levels, and cognitive decline were correlated with the number of lobar cerebral microbleeds in Alzheimer’s disease patients ( P < 0.001). Conclusion Lobar distribution of cerebral microbleeds is associated with Alzheimer’s disease and the number of lobar cerebral microbleeds directly correlates with cerebrospinal fluid amyloid-beta and phosphorylated tau 181 protein levels and with the cognitive decline of Alzheimer’s disease patients.
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Rahman, Md Saidur, Md Nazmul Hasan Zilani, Md Aminul Islam, Md Munaib Hasan, Md Muzahidul Islam, Farzana Yasmin, Partha Biswas et al. « In Vivo Neuropharmacological Potential of Gomphandra tetrandra (Wall.) Sleumer and In-Silico Study against β-Amyloid Precursor Protein ». Processes 9, no 8 (20 août 2021) : 1449. http://dx.doi.org/10.3390/pr9081449.
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Medicinal plants possess a surplus of novel and biologically active secondary metabolites that are responsible for counteracting diseases. Traditionally, Gomphandra tetrandra (Wall.) Sleumer is used to treat mental disorders. The present research was designed to explore phytochemicals from the ethanol leaf extract of Gomphandra tetrandra (Wall.) Sleumer to identify the potential pharmacophore(s) in the treatment of neurological disorders. The chemical compounds of the experimental plant were identified through GC-MS analysis. In-vitro antioxidant activity was assessed using different methods. Furthermore, in-vivo neurological activity was assessed in Swiss-albino mice. Computer-aided analysis was appraised to determine the best-fit phytoconstituent of a total of fifteen identified compounds in the experimental plant extract against beta-amyloid precursor protein. The experimental extract revealed fifteen compounds in GC-MS analysis and the highest content was 9, 12, 15-octadecatrienoic acid (z,z,z). The extract showed potent antioxidant activity in in-vitro assays. Furthermore, in in-vivo neurological assays, the extract disclosed significant (p < 0.05) neurological activity. The most favorable phytochemicals as neurological agents were selected via ADMET profiling, and molecular docking was studied with beta-amyloid precursor protein. In the computer-aided study, 1, 5-diphenyl-2h-1, 2, 4-triazoline-3-thione (Pub Chem CID: 2802516) was more active than other identified compounds with strong binding affinity to beta-amyloid precursor protein. The present in vivo and in silico studies revealed neuropharmacological features of G. tetrandra leaf extract as a natural agent against neurological disorders, especially Alzheimer’s disease.
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Ran, Kathleen, Jing Yang, Anil V. Nair, Biyue Zhu et Chongzhao Ran. « CRANAD-28 : A Robust Fluorescent Compound for Visualization of Amyloid Beta Plaques ». Molecules 25, no 4 (16 février 2020) : 863. http://dx.doi.org/10.3390/molecules25040863.
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CRANAD-28, a difluoroboron curcumin analogue, has been demonstrated in earlier reports to successfully label amyloid beta (Aβ) plaques for imaging both ex vivo and in vivo. CRANAD-28’s imaging brightness, ability to penetrate the blood brain barrier, and low toxicity make the compound a potentially potent imaging tool in Alzheimer’s research. In this study, the Aβ-labeling ability of CRANAD-28 was investigated in further detail using histological staining to assess different criteria, including stained Aβ plaque brightness, Aβ plaque size, and Aβ plaque number count. The results of this study demonstrated CRANAD-28 to be superior across all criteria assessed. Furthermore, CRANAD-28 and IBA-1 antibody were used to label Aβ-plaques and microglia respectively. Statistical analysis with Spearman regression revealed a statistically significant negative correlation between the size of labeled Aβ plaques and surrounding microglia density. This finding provides interesting insight into Aβ plaque and microglia dynamism in AD pathology and corroborates the findings of previous studies. In addition, we found that CRANAD-28 provided distinct spectral signatures for Aβs in the core and periphery of the plaques. Based on the study’s results, CRANAD-28 could be considered as an alternative standard for imaging Aβ-plaques in future research studies.
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Steinhilb, Michelle L., R. Scott Turner et James R. Gaut. « ELISA analysis of beta-secretase cleavage of the Swedish amyloid precursor protein in the secretory and endocytic pathways ». Journal of Neurochemistry 80, no 6 (mars 2002) : 1019–28. http://dx.doi.org/10.1046/j.0022-3042.2002.00764.x.
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Gesperger, Johanna, Antonia Lichtenegger, Thomas Roetzer, Marco Augustin, Danielle J. Harper, Pablo Eugui, Conrad W. Merkle, Christoph K. Hitzenberger, Adelheid Woehrer et Bernhard Baumann. « Comparison of Intensity- and Polarization-based Contrast in Amyloid-beta Plaques as Observed by Optical Coherence Tomography ». Applied Sciences 9, no 10 (22 mai 2019) : 2100. http://dx.doi.org/10.3390/app9102100.
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One key hallmark of Alzheimer’s disease (AD) is the accumulation of extracellular amyloid-beta protein in cortical regions of the brain. For a definitive diagnosis of AD, post-mortem histological analysis, including sectioning and staining of different brain regions, is required. Here, we present optical coherence tomography (OCT) as a tissue-preserving imaging modality for the visualization of amyloid-beta plaques and compare their contrast in intensity- and polarization-sensitive (PS) OCT. Human brain samples of eleven patients diagnosed with AD were imaged. Three-dimensional PS-OCT datasets were acquired and plaques were manually segmented in 500 intensity and retardation cross-sections per patient using the freely available ITK-SNAP software. The image contrast of plaques was quantified. Histological staining of tissue sections from the same specimens was performed to compare OCT findings against the gold standard. Furthermore, the distribution of plaques was evaluated for intensity-based OCT, PS-OCT and the corresponding histological amyloid-beta staining. Only 5% of plaques were visible in both intensity and retardation segmentations, suggesting that different types of plaques may be visualized by the two OCT contrast channels. Our results indicate that multicontrast OCT imaging might be a promising approach for a tissue-preserving visualization of amyloid-beta plaques in AD.
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Almeida, Michael F., Carolliny M. Silva, Aline M. D’Unhao et Merari F. R. Ferrari. « Aged Lewis rats exposed to low and moderate doses of rotenone are a good model for studying the process of protein aggregation and its effects upon central nervous system cell physiology ». Arquivos de Neuro-Psiquiatria 74, no 9 (septembre 2016) : 737–44. http://dx.doi.org/10.1590/0004-282x20160121.
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ABSTRACT Cell physiology is impaired before protein aggregation and this may be more relevant than inclusions themselves for neurodegeneration. The present study aimed to characterize an animal model to enable the analysis of the cell biology before and after protein aggregation. Ten-month-old Lewis rats were exposed either to 1 or 2 mg/kg/day of rotenone, delivered subcutaneously through mini-pumps, for one month. Hyperphosphorylated TAU, alpha-synuclein, amyloid-beta peptide and protein carbonylation (indicative of oxidative stress) were evaluated in the hippocampus, substantia nigra and locus coeruleus through immunohistochemistry or western blot. It was found that 2 mg/kg/day rotenone increased amyloid-beta peptide, hyperphosphorylation of TAU and alpha-synuclein. Rotenone at 1mg/kg/day did not alter protein levels. Protein carbonylation remained unchanged. This study demonstrated that aged Lewis rats exposed to a low dose of rotenone is a useful model to study cellular processes before protein aggregation, while the higher dose makes a good model to study the effects of protein inclusions.
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Ong, Lin Kooi, Zidan Zhao, Murielle Kluge, Frederick R. Walker et Michael Nilsson. « Chronic stress exposure following photothrombotic stroke is associated with increased levels of Amyloid beta accumulation and altered oligomerisation at sites of thalamic secondary neurodegeneration in mice ». Journal of Cerebral Blood Flow & ; Metabolism 37, no 4 (20 juillet 2016) : 1338–48. http://dx.doi.org/10.1177/0271678x16654920.
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Exposure to severe stress following stroke is recognised to complicate the recovery process. We have identified that stress can exacerbate the severity of post-stroke secondary neurodegeneration in the thalamus. In this study, we investigated whether exposure to stress could influence the accumulation of the neurotoxic protein Amyloid-β. Using an experimental model of focal cortical ischemia in adult mice combined with exposure to chronic restraint stress, we examined changes within the contra- and ipsilateral thalamus at six weeks post-stroke using Western blotting and immunohistochemical approaches. Western blotting analysis indicated that stroke was associated with a significant enhancement of the 25 and 50 kDa oligomers within the ipsilateral hemisphere and the 20 kDa oligomer within the contralateral hemisphere. Stroked animals exposed to stress exhibited an additional increase in multiple forms of Amyloid-beta oligomers. Immunohistochemistry analysis confirmed that stroke was associated with a significant accumulation of Amyloid-beta within the thalami of both hemispheres, an effect that was exacerbated in stroke animals exposed to stress. Given that Amyloid-beta oligomers, most notably the 30–40 and 50 kDa oligomers, are recognised to correlate with accelerated cognitive decline, our results suggest that monitoring stress levels in patients recovering from stroke may merit consideration in the future.
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Cater, Jordan H., Janet R. Kumita, Rafaa Zeineddine Abdallah, Guomao Zhao, Ana Bernardo-Gancedo, Amanda Henry, Wendy Winata et al. « Human pregnancy zone protein stabilizes misfolded proteins including preeclampsia- and Alzheimer’s-associated amyloid beta peptide ». Proceedings of the National Academy of Sciences 116, no 13 (8 mars 2019) : 6101–10. http://dx.doi.org/10.1073/pnas.1817298116.
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Protein misfolding underlies the pathology of a large number of human disorders, many of which are age-related. An exception to this is preeclampsia, a leading cause of pregnancy-associated morbidity and mortality in which misfolded proteins accumulate in body fluids and the placenta. We demonstrate that pregnancy zone protein (PZP), which is dramatically elevated in maternal plasma during pregnancy, efficiently inhibits in vitro the aggregation of misfolded proteins, including the amyloid beta peptide (Aβ) that is implicated in preeclampsia as well as with Alzheimer’s disease. The mechanism by which this inhibition occurs involves the formation of stable complexes between PZP and monomeric Aβ or small soluble Aβ oligomers formed early in the aggregation pathway. The chaperone activity of PZP is more efficient than that of the closely related protein alpha-2-macroglobulin (α2M), although the chaperone activity of α2M is enhanced by inducing its dissociation into PZP-like dimers. By immunohistochemistry analysis, PZP is found primarily in extravillous trophoblasts in the placenta. In severe preeclampsia, PZP-positive extravillous trophoblasts are adjacent to extracellular plaques containing Aβ, but PZP is not abundant within extracellular plaques. Our data support the conclusion that the up-regulation of PZP during pregnancy represents a major maternal adaptation that helps to maintain extracellular proteostasis during gestation in humans. We propose that overwhelming or disrupting the chaperone function of PZP could underlie the accumulation of misfolded proteins in vivo. Attempts to characterize extracellular proteostasis in pregnancy will potentially have broad-reaching significance for understanding disease-related protein misfolding.
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Chrystal, Paul W., Tim Footz, Elizabeth D. Hodges, Justin A. Jensen, Michael A. Walter et W. Ted Allison. « Functional Domains and Evolutionary History of the PMEL and GPNMB Family Proteins ». Molecules 26, no 12 (9 juin 2021) : 3529. http://dx.doi.org/10.3390/molecules26123529.
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The ancient paralogs premelanosome protein (PMEL) and glycoprotein nonmetastatic melanoma protein B (GPNMB) have independently emerged as intriguing disease loci in recent years. Both proteins possess common functional domains and variants that cause a shared spectrum of overlapping phenotypes and disease associations: melanin-based pigmentation, cancer, neurodegenerative disease and glaucoma. Surprisingly, these proteins have yet to be shown to physically or genetically interact within the same cellular pathway. This juxtaposition inspired us to compare and contrast this family across a breadth of species to better understand the divergent evolutionary trajectories of two related, but distinct, genes. In this study, we investigated the evolutionary history of PMEL and GPNMB in clade-representative species and identified TMEM130 as the most ancient paralog of the family. By curating the functional domains in each paralog, we identified many commonalities dating back to the emergence of the gene family in basal metazoans. PMEL and GPNMB have gained functional domains since their divergence from TMEM130, including the core amyloid fragment (CAF) that is critical for the amyloid potential of PMEL. Additionally, the PMEL gene has acquired the enigmatic repeat domain (RPT), composed of a variable number of imperfect tandem repeats; this domain acts in an accessory role to control amyloid formation. Our analyses revealed the vast variability in sequence, length and repeat number in homologous RPT domains between craniates, even within the same taxonomic class. We hope that these analyses inspire further investigation into a gene family that is remarkable from the evolutionary, pathological and cell biology perspectives.