Artykuły w czasopismach: „Prion amyloidogenesis”

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Kinoshita, Misaki, Yuxi Lin, Masatoshi Nakatsuji, Takashi Inui i Young-Ho Lee. "Kinetics and polymorphs of yeast prion Sup35NM amyloidogenesis". International Journal of Biological Macromolecules 102 (wrzesień 2017): 1241–49. http://dx.doi.org/10.1016/j.ijbiomac.2017.05.001.

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Shirasaka, Maki, Kazuo Kuwata i Ryo Honda. "α-Synuclein chaperone suppresses nucleation and amyloidogenesis of prion protein". Biochemical and Biophysical Research Communications 521, nr 1 (styczeń 2020): 259–64. http://dx.doi.org/10.1016/j.bbrc.2019.10.120.

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Schininà, M. E., Bruno Maras, Franco Cardone, Carmine Mancone, S. Principe, M. A. Di Bari, P. Parchi i M. Pocchiari. "Prion protein allotype profiling by mass spectrometry". Pure and Applied Chemistry 75, nr 2-3 (1.01.2003): 317–23. http://dx.doi.org/10.1351/pac200375020317.

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Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative pathologies characterized by the formation in the central nervous system of the amyloid protein PrPSc, which derives from a cellular precursor called PrPc. Epidemiological and laboratory studies have shown that in species where the PrPc gene is polymorphic, the genotype composition is an important factor for the development of the disease. Identification of PrPSc allotypes accumulated in the brain during the disease proved valuable to investigate whether these polymorphisms are critical for the pathological conversion. These analyses are complicated by the heterogeneity and the insolubility of the prion amyloid extracted from affected brains, which have been obviated by extensive digestion of extracted fractions and analysis of peptide fragment composition. We have developed an optimized protocol of liquid chromatography/mass spectrometry (LC/MS) that can reliably map PrP peptides in digested fractions with a low PrPSc/contaminants ratio. This approach has been successfully applied to the analysis of amyloidogenesis in experimentally infected PrP-heterozygous laboratory animals.

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Saiki, Masatoshi, Yuji Hidaka, Masayuki Nara i Hisayuki Morii. "Stem-Forming Regions That Are Essential for the Amyloidogenesis of Prion Proteins". Biochemistry 51, nr 8 (16.02.2012): 1566–76. http://dx.doi.org/10.1021/bi201688r.

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Tcherkasskaya, Olga, William Sanders, Veeradej Chynwat, Eugene A. Davidson i Cindy S. Orser. "The Role of Hydrophobic Interactions in Amyloidogenesis: Example of Prion-Related Polypeptides". Journal of Biomolecular Structure and Dynamics 21, nr 3 (grudzień 2003): 353–65. http://dx.doi.org/10.1080/07391102.2003.10506931.

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Berthelot, Karine, Sophie Lecomte, Julie Géan, Françoise Immel i Christophe Cullin. "A Yeast Toxic Mutant of HET-s(218-289) Prion Displays Alternative Intermediates of Amyloidogenesis". Biophysical Journal 99, nr 4 (sierpień 2010): 1239–46. http://dx.doi.org/10.1016/j.bpj.2010.06.015.

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Oroz, Javier, Sara S. Félix, Eurico J. Cabrita i Douglas V. Laurents. "Structural transitions in Orb2 prion-like domain relevant for functional aggregation in memory consolidation". Journal of Biological Chemistry 295, nr 52 (22.10.2020): 18122–33. http://dx.doi.org/10.1074/jbc.ra120.015211.

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The recent structural elucidation of ex vivo Drosophila Orb2 fibrils revealed a novel amyloid formed by interdigitated Gln and His residue side chains belonging to the prion-like domain. However, atomic-level details on the conformational transitions associated with memory consolidation remain unknown. Here, we have characterized the nascent conformation and dynamics of the prion-like domain (PLD) of Orb2A using a nonconventional liquid-state NMR spectroscopy strategy based on 13C detection to afford an essentially complete set of 13Cα, 13Cβ, 1Hα, and backbone 13CO and 15N assignments. At pH 4, where His residues are protonated, the PLD is disordered and flexible, except for a partially populated α-helix spanning residues 55–60, and binds RNA oligos, but not divalent cations. At pH 7, in contrast, His residues are predominantly neutral, and the Q/H segments adopt minor populations of helical structure, show decreased mobility and start to self-associate. At pH 7, the His residues do not bind RNA or Ca2+, but do bind Zn2+, which promotes further association. These findings represent a remarkable case of structural plasticity, based on which an updated model for Orb2A functional amyloidogenesis is suggested.

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Yamashita, Satoshi, Yuji O. Kamatari, Ryo Honda, Ayumi Niwa, Hiroyuki Tomiata, Akira Hara i Kazuo Kuwata. "Monomeric α-synuclein (αS) inhibits amyloidogenesis of human prion protein (hPrP) by forming a stable αS-hPrP hetero-dimer." Prion 15, nr 1 (1.01.2021): 37–43. http://dx.doi.org/10.1080/19336896.2021.1910176.

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Paramasivam, Santhosh, Kavita Kundal i Nandini Sarkar. "Human Serum Albumin Aggregation and its Modulation Using Nanoparticles: A Review". Protein & Peptide Letters 29, nr 1 (styczeń 2022): 11–21. http://dx.doi.org/10.2174/0929866528666211125104600.

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: Amyloid fibrils are highly stable protein fibrillar aggregates believed to be involved in various neurodegenerative diseases, which include Alzheimer’s disease, Parkinson’s disease, and prion diseases. Inhibiting the aggregation process is a potential strategy to prevent diseases caused by amyloid formation. In this regard, nanoparticles have emerged as promising candidates owing to their unique physical/chemical properties of small size, large surface area, biocompatibility, biodegradability, non-toxicity, and ease of functionalization. Human Serum Albumin (HSA) is a soluble multidomain monomeric protein that interacts with various ligands and hormones, aiding in their transport, distribution, metabolism in the circulatory system, and also plays a vital role in extracellular fluid volume stabilization. Under certain in vitro conditions, HSA has been reported to undergo conformational changes leading to fibril formation and hence acts as a suitable model for studying amyloidogenesis. In this review, we have explored the effects of various nanoparticles on HSA aggregation and their mechanism of action. The study will throw light on the mechanistic details of nanoparticle-mediated amyloid modulation, which will help in the development of effective therapeutics against amyloidosis.

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Zhang, Wei, Minghui Zhang, Qin Wu i Jingshan Shi. "Dendrobium nobile Lindl. Alkaloids Ameliorate Aβ25-35-Induced Synaptic Deficits by Targeting Wnt/β-Catenin Pathway in Alzheimer’s Disease Models". Journal of Alzheimer's Disease 86, nr 1 (8.03.2022): 297–313. http://dx.doi.org/10.3233/jad-215433.

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Background: Dendrobium nobile Lindl. alkaloids (DNLA) are effective in ameliorating cognitive deficit in SAMP8, AβPP/PS1, and LPS-induced AD animal models, and prevented Aβ-induced synaptic degeneration in cultured hippocampal neurons. However, the underlying mechanisms remain unexplored. Objective: This study investigated the protective effects of DNLA on synaptic damage in an Aβ25-35-induced rat AD model, in primary cortical neuron cultures, and in PC12 cells transfected with human AβPP695, focusing on the Wnt/β-catenin pathway. Methods: Sprague-Dawley rats received a single Aβ25-35 injection (10μg) into the bilateral hippocampi. DNLA (40 and 80 mg/kg/d) was intragastrically administrated 7 days prior to Aβ injection and continued for 28 days. The spatial learning and memory, synaptic morphology, synapse-related proteins, and Wnt signaling components GSK3β and β-catenin phosphorylation were evaluated. Rat primary cortical neuron cultures and AβPP695-PC12 cells were used to evaluate axonal mitochondria distribution, reactive oxygen species production, amyloidogenesis, and Wnt pathway in the protection. Results: DNLA ameliorated Aβ-induced cognitive impairment, increased the number of synapses, elevated the postsynaptic density thickness and expression of synapsin and PSD95 in the hippocampus, and suppressed Aβ-mediated GSK3β activity and the β-catenin phosphorylation. In primary neurons and AβPP695-PC12 cells, DNLA restored Aβ25-35 induced mitochondrial dysfunction and inhibited reactive oxygen species production and amyloidogenesis. Furthermore, the Wnt/β-catenin pathway inhibitor Dkk-1 blocked the effect of DNLA on the expression of Aβ1-42 and PSD95. Conclusion: DNLA rescued Aβ-mediated synaptic and mitochondrial injury and inhibited amyloidogenesis in vivo and in vitro, probably through the activation of Wnt/β-catenin signaling pathway to protect synaptic integrity.

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Sanders, Anna, C. Jeremy Craven, Lee D. Higgins, Silva Giannini, Matthew J. Conroy, Andrea M. Hounslow, Jonathan P. Waltho i Rosemary A. Staniforth. "Cystatin forms a Tetramer through Structural Rearrangement of Domain-swapped Dimers prior to Amyloidogenesis". Journal of Molecular Biology 336, nr 1 (luty 2004): 165–78. http://dx.doi.org/10.1016/j.jmb.2003.12.011.

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Galkin, Alexey P., i Evgeniy I. Sysoev. "Stress Response Is the Main Trigger of Sporadic Amyloidoses". International Journal of Molecular Sciences 22, nr 8 (15.04.2021): 4092. http://dx.doi.org/10.3390/ijms22084092.

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Amyloidoses are a group of diseases associated with the formation of pathological protein fibrils with cross-β structures. Approximately 5–10% of the cases of these diseases are determined by amyloidogenic mutations, as well as by transmission of infectious amyloids (prions) between organisms. The most common group of so-called sporadic amyloidoses is associated with abnormal aggregation of wild-type proteins. Some sporadic amyloidoses are known to be induced only against the background of certain pathologies, but in some cases the cause of amyloidosis is unclear. It is assumed that these diseases often occur by accident. Here we present facts and hypotheses about the association of sporadic amyloidoses with vascular pathologies, trauma, oxidative stress, cancer, metabolic diseases, chronic infections and COVID-19. Generalization of current data shows that all sporadic amyloidoses can be regarded as a secondary event occurring against the background of diseases provoking a cellular stress response. Various factors causing the stress response provoke protein overproduction, a local increase in the concentration or modifications, which contributes to amyloidogenesis. Progress in the treatment of vascular, metabolic and infectious diseases, as well as cancers, should lead to a significant reduction in the risk of sporadic amyloidoses.

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Vashist, Shilpa, Mimi Cushman i James Shorter. "Applying Hsp104 to protein-misfolding disordersThis paper is one of a selection of papers published in this special issue entitled 8th International Conference on AAA Proteins and has undergone the Journal's usual peer review process." Biochemistry and Cell Biology 88, nr 1 (luty 2010): 1–13. http://dx.doi.org/10.1139/o09-121.

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Hsp104, a hexameric AAA+ ATPase found in yeast, transduces energy from cycles of ATP binding and hydrolysis to resolve disordered protein aggregates and cross-β amyloid conformers. These disaggregation activities are often co-ordinated by the Hsp70 chaperone system and confer considerable selective advantages. First, renaturation of aggregated conformers by Hsp104 is critical for yeast survival after various environmental stresses. Second, amyloid remodeling by Hsp104 enables yeast to exploit multifarious prions as a reservoir of beneficial and heritable phenotypic variation. Curiously, although highly conserved in plants, fungi and bacteria, Hsp104 orthologues are absent from metazoa. Indeed, metazoan proteostasis seems devoid of a system that couples protein disaggregation to renaturation. Here, we review recent endeavors to enhance metazoan proteostasis by applying Hsp104 to the specific protein-misfolding events that underpin two deadly neurodegenerative amyloidoses. Hsp104 potently inhibits Aβ42 amyloidogenesis, which is connected with Alzheimer’s disease, but appears unable to disaggregate preformed Aβ42 fibers. By contrast, Hsp104 inhibits and reverses the formation of α-synuclein oligomers and fibers, which are connected to Parkinson’s disease. Importantly, Hsp104 antagonizes the degeneration of dopaminergic neurons induced by α-synuclein misfolding in the rat substantia nigra. These studies raise hopes for developing Hsp104 as a therapeutic agent.

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Huang, Alexis S., Benjamin C. K. Tong, Aston J. Wu, Xiaotong Chen, Sravan G. Sreenivasmurthy, Zhou Zhu, Jia Liu, Chengfu Su, Min Li i King-Ho Cheung. "Rectifying Attenuated Store-Operated Calcium Entry as a Therapeutic Approach for Alzheimer’s Disease". Current Alzheimer Research 17, nr 12 (22.02.2021): 1072–87. http://dx.doi.org/10.2174/1567205018666210119150613.

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: Alzheimer’s disease (AD) is the most common neurodegenerative disorder. Although the pathological hallmarks of AD have been identified, the derived therapies cannot effectively slow down or stop disease progression; hence, it is likely that other pathogenic mechanisms are involved in AD pathogenesis. Intracellular calcium (Ca2+) dyshomeostasis has been consistently observed in AD patients and numerous AD models and may emerge prior to the development of amyloid plaques and neurofibrillary tangles. Thus, intracellular Ca2+ disruptions are believed to play an important role in AD development and could serve as promising therapeutic intervention targets. : One of the disrupted intracellular Ca2+ signaling pathways manifested in AD is attenuated storeoperated Ca2+ entry (SOCE). SOCE is an extracellular Ca2+ entry mechanism mainly triggered by intracellular Ca2+ store depletion. Maintaining normal SOCE function not only provides a means for the cell to replenish ER Ca2+ stores but also serves as a cellular signal that maintains normal neuronal functions, including excitability, neurogenesis, neurotransmission, synaptic plasticity, and gene expression. However, normal SOCE function is diminished in AD, resulting in disrupted neuronal spine stability and synaptic plasticity and the promotion of amyloidogenesis. Mounting evidence suggests that rectifying diminished SOCE in neurons may intervene with the progression of AD. In this review, the mechanisms of SOCE disruption and the associated pathogenic impacts on AD will be discussed. We will also highlight the potential therapeutic targets or approaches that may help ameliorate SOCE deficits for AD treatment.

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Dookhy, Joshi, Cathy McHale, Sean Kennelly, Tara Coughlan, Ronan Collins, Dan Ryan i Desmond O'Neill. "127 Modifiable Cardiovascular Risk Profile in People with Mild Cognitive Symptoms Attending a Memory Service - an Opportunity to Promote Brain Health". Age and Ageing 48, Supplement_3 (wrzesień 2019): iii17—iii65. http://dx.doi.org/10.1093/ageing/afz103.75.

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Abstract Background Current evidence strongly implicates the burden of vascular risk factors (VRF) in the development of stroke, cognitive decline and dementia. This effect is mediated through several mechanisms, including amyloidogenesis, chronic neuroinflamation, cerebral perfusion and white-matter changes. Vascular risk profiling is well-embedded in stroke and cardiac services, but less so in memory services. Methods A review of established modifiable VRF (hypercholesterolemia, Body Mass Index (BMI), hypertension, HbA1c, smoking and alcohol habits) of people with mild cognitive complaints (mild cognitive impairment and subjective memory decline) in a memory service was performed. Risk factors measured in clinic were classified as: systolic ≥140mmHg / diastolic ≥90mmHg hypertension; LDL cholesterol >3mmol/l; HbA1c >39mmol/mol; weekly alcohol >21units; smoking and BMI >24.9kg/m2. Data was recorded and analysed using Microsoft Excel. Results Thirty-seven people, including 16 females (mean age 71.4, range of 49-83 years), were reviewed. 13/37 (35%) were aged ≤69 years. A total of 91 VRFs were identified in the study population. 29/37 (78%) had ≥2 VRF present. 3/37 (8%) had five VRF. 18/37 (49%) had prior history of either stroke, vascular or heart disease. Five of thirty-seven, (13.5%) and 13/37 (35%) were current and ex-smokers respectively, 2/37 (5%) consumed excess alcohol, 24/37 (65%) had elevated BMI and 11/37 (30%) had elevated LDL cholesterol. 21/37 (57%) had hypertension. Of these, 11/21 were known but poorly-controlled and 10/21 were identified de novo. All of the 32% (12/37) who had hyperglycaemia were de novo. Conclusion This study highlights the high prevalence of unidentified or poorly controlled VRF in people with mild cognitive symptoms attending a memory service. Given its importance to brain health and mitigation of future cognitive decline, a structured focus on identifying and managing these VRF in this setting is necessary. Exercise-based lifestyle programs should be embedded in post-diagnostic services for this population.

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Stępkowski, Dariusz, i Juliusz Bieniaś. "Nature of cross-seeding barriers of amyloidogenesis." Acta Biochimica Polonica 59, nr 2 (11.05.2012). http://dx.doi.org/10.18388/abp.2012_2156.

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The epidemics of bovine spongiform encephalopathy (BSE) several decades ago and present epidemics of chronic wasting disease (CWD) among cervids posed a threat of cross-species infections to humans or other animals. Therefore, the question as to the molecular nature of the species barriers to transmissibility of prion diseases is very important. We approached this problem theoretically, first developing a model of template-monomer interaction based on logical and topological grounds and on experimental data about cross-seeding of PrP 23-144 protein orthologs. Further, we propose that the strength of the cross-seeding barriers is proportional to dissimilarity of key amyloidogenic regions of the proteins. This dissimilarity can be measured by dissimilarity function we propose. Scaled on experimental data, this function predicts if cross-seeding can occur between different variants of PrP23-144. The resemblance of PrP23-144 cross-seeding barriers to the barriers of cross-species transmissibility of prion diseases is discussed. We suggest that a similar theoretical approach could be applied to predicting the occurrence of species barriers of prion diseases at least in part corresponding to the process of multiplication of infectious agent.

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Revilla-García, Aida, Cristina Fernández, María Moreno-del Álamo, Vivian de los Ríos, Ina M. Vorberg i Rafael Giraldo. "Intercellular Transmission of a Synthetic Bacterial Cytotoxic Prion-Like Protein in Mammalian Cells". mBio 11, nr 2 (14.04.2020). http://dx.doi.org/10.1128/mbio.02937-19.

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ABSTRACT RepA is a bacterial protein that builds intracellular amyloid oligomers acting as inhibitory complexes of plasmid DNA replication. When carrying a mutation enhancing its amyloidogenesis (A31V), the N-terminal domain (WH1) generates cytosolic amyloid particles that are inheritable within a bacterial lineage. Such amyloids trigger in bacteria a lethal cascade reminiscent of mitochondrial impairment in human cells affected by neurodegeneration. To fulfill all the criteria to qualify as a prion-like protein, horizontal (intercellular) transmissibility remains to be demonstrated for RepA-WH1. Since this is experimentally intractable in bacteria, here we transiently expressed in a murine neuroblastoma cell line the soluble, barely cytotoxic RepA-WH1 wild type [RepA-WH1(WT)] and assayed its response to exposure to in vitro-assembled RepA-WH1(A31V) amyloid fibers. In parallel, murine cells releasing RepA-WH1(A31V) aggregates were cocultured with human neuroblastoma cells expressing RepA-WH1(WT). Both the assembled fibers and donor-derived RepA-WH1(A31V) aggregates induced, in the cytosol of recipient cells, the formation of cytotoxic amyloid particles. Mass spectrometry analyses of the proteomes of both types of injured cells pointed to alterations in mitochondria, protein quality triage, signaling, and intracellular traffic. Thus, a synthetic prion-like protein can be propagated to, and become cytotoxic to, cells of organisms placed at such distant branches of the tree of life as bacteria and mammalia, suggesting that mechanisms of protein aggregate spreading and toxicity follow default pathways. IMPORTANCE Proteotoxic amyloid seeds can be transmitted between mammalian cells, arguing that the intercellular exchange of prion-like protein aggregates can be a common phenomenon. RepA-WH1 is derived from a bacterial intracellular functional amyloid protein, engineered to become cytotoxic in Escherichia coli. Here, we have studied if such bacterial aggregates can also be transmitted to, and become cytotoxic to, mammalian cells. We demonstrate that RepA-WH1 is capable of entering naive cells, thereby inducing the cytotoxic aggregation of a soluble RepA-WH1 variant expressed in the cytosol, following the same trend that had been described in bacteria. These findings highlight the universality of one of the central principles underlying prion biology: No matter the biological origin of a given prion-like protein, it can be transmitted to a phylogenetically unrelated recipient cell, provided that the latter expresses a soluble protein onto which the incoming protein can readily template its amyloid conformation.

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Bengoa-Vergniory, Nora, Elisavet Velentza-Almpani, Ana Maria Silva, Connor Scott, Mariana Vargas-Caballero, Magdalena Sastre, Richard Wade-Martins i Javier Alegre-Abarrategui. "Tau-proximity ligation assay reveals extensive previously undetected pathology prior to neurofibrillary tangles in preclinical Alzheimer’s disease". Acta Neuropathologica Communications 9, nr 1 (28.01.2021). http://dx.doi.org/10.1186/s40478-020-01117-y.

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Abstract Background Multimerization is a key process in prion-like disorders such as Alzheimer’s disease (AD), since it is a requirement for self-templating tau and beta-amyloid amyloidogenesis. AT8-immunohistochemistry for hyperphosphorylated tau is currently used for the diagnosis and staging of tau pathology. Given that tau–tau interactions can occur in the absence of hyperphosphorylation or other post-translational modifications (PTMs), the direct visualization of tau multimerization could uncover early pathological tau multimers. Methods Here, we used bimolecular fluorescent complementation, rapamycin-dependent FKBP/FRB-tau interaction and transmission electron microscopy to prove the in vitro specificity of tau-proximity ligation assay (tau-PLA). We then analyzed MAPT KO and P301S transgenic mice, and human hippocampus and temporal isocortex of all Braak stages with tau-PLA and compared it with immunohistochemistry for the diagnostic antibody AT8, the early phosphorylation-dependent AT180, and the conformational-dependent antibody MC1. Finally, we performed proteinase-K treatment to infer the content of amyloidogenic beta-sheet fold. Results Our novel tau-proximity ligation assay (tau-PLA) directly visualized tau–tau interactions in situ, and exclusively recognized tau multimers but not monomers. It elicited no signal in MAPT KO mouse brains, but extensively labelled P301S transgenic mice and AD brain. Two groups of structures were detected, a previously unreported widespread small-sized diffuse pathology and large, neurofibrillary-like lesions. Tau-PLA-labelled diffuse pathology appeared from the earliest Braak stages, mostly unaccompanied by tangle-like tau-immunohistochemistry, being significantly more sensitive than any small-sized dot-/thread-like pathology labelled by AT180-, AT8- and MC1-immunohistochemistry in most regions quantified at stages 0-II. Tau-PLA-labelled diffuse pathology was extremely sensitive to Proteinase-K, in contrast to large lesions. Conclusions Tau-PLA is the first method to directly visualize tau multimers both in vitro and in situ with high specificity. We find that tau multimerization appears extensively from the earliest presymptomatic Braak stages as a previously unreported type of diffuse pathology. Importantly, in our study multimerization is the earliest detectable molecular event of AD tau pathology. Our findings open a new window to the study of early tau pathology, with potential implications in early diagnosis and the design of therapeutic strategies.

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Prosswimmer, Tatum, i Valerie Daggett. "The role of α-sheet structure in amyloidogenesis: characterization and implications". Open Biology 12, nr 11 (listopad 2022). http://dx.doi.org/10.1098/rsob.220261.

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Amyloid diseases are linked to protein misfolding whereby the amyloidogenic protein undergoes a conformational change, aggregates and eventually forms amyloid fibrils. While the amyloid fibrils and plaques are hallmarks of these diseases, they typically form late in the disease process and do not correlate with disease. Instead, there is growing evidence that smaller, soluble toxic oligomers form prior and appear to be early triggers of the molecular pathology underlying these diseases. Nearly 20 years ago, we proposed the α-sheet hypothesis after discovering that the early conformational changes observed during atomistic molecular dynamics simulations involve the formation of a non-standard protein structure, α-sheet. Furthermore, we proposed that toxic oligomers contain α-sheet structure and that preferentially targeting this structure could neutralize the toxicity, prevent further aggregation and serve as the basis for early detection of disease. Here, we present the origin of the α-sheet hypothesis and describe α-sheet structure and the corresponding mechanisms of conversion. We discuss experimental studies demonstrating that both mammalian and bacterial amyloid systems form α-sheet oligomers before converting to conventional β-sheet fibrils. Furthermore, we show that the process can be inhibited with de novo designed α-sheet peptides complementary to the structure in the toxic oligomers.

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McMackin, Patrick, Joe Adam, Shannon Griffin i Amir Hirsa. "Amyloidogenesis via interfacial shear in a containerless biochemical reactor aboard the International Space Station". npj Microgravity 8, nr 1 (20.09.2022). http://dx.doi.org/10.1038/s41526-022-00227-2.

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AbstractFluid interfaces significantly influence the dynamics of protein solutions, effects that can be isolated by performing experiments in microgravity, greatly reducing the amount of solid boundaries present, allowing air-liquid interfaces to become dominant. This investigation examined the effects of protein concentration on interfacial shear-induced fibrillization of insulin in microgravity within a containerless biochemical reactor, the ring-sheared drop (RSD), aboard the international space station (ISS). Human insulin was used as a model amyloidogenic protein for studying protein kinetics with applications to in situ pharmaceutical production, tissue engineering, and diseases such as Alzheimer’s, Parkinson’s, infectious prions, and type 2 diabetes. Experiments investigated three main stages of amyloidogenesis: nucleation studied by seeding native solutions with fibril aggregates, fibrillization quantified using intrinsic fibrillization rate after fitting measured solution intensity to a sigmoidal function, and gelation observed by detection of solidification fronts. Results demonstrated that in surface-dominated amyloidogenic protein solutions: seeding with fibrils induces fibrillization of native protein, intrinsic fibrillization rate is independent of concentration, and that there is a minimum fibril concentration for gelation with gelation rate and rapidity of onset increasing monotonically with increasing protein concentration. These findings matched well with results of previous studies within ground-based analogs.

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van Hulst, KL, C. Oosterwijk, W. Born, TM Vroom, MG Nieuwenhuis, MA Blankenstein, CJ Lips, JA Fischer i JW Hoppener. "Islet amyloid polypeptide/amylin messenger RNA and protein expression in human insulinomas in relation to amyloid formation". European Journal of Endocrinology, 1.01.1999, 69–78. http://dx.doi.org/10.1530/eje.0.1400069.

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OBJECTIVE: Islet amyloid polypeptide (IAPP), also named amylin, is the predominant protein component of amyloid deposits in human islet beta cell tumours of the pancreas (insulinomas). IAPP is co-produced with insulin by islet beta cells. We investigated IAPP expression in relation to insulin expression and to amyloid formation in eleven insulinomas. DESIGN AND METHODS: RNA and protein extracts were prepared from the same pieces of tumour tissue, and from specimens of two normal human pancreata. IAPP and insulin mRNA and peptide content were quantified using Northern blot analysis and radioimmunoassay (RIA) respectively. Molecular forms of IAPP immunoreactivity were analysed by reversed-phase high-performance liquid chromatography (HPLC). The presence of islet hormones and of amyloid was assessed by (immuno)histochemical staining of paraffin sections. Plasma levels of IAPP and insulin prior to tumour resection were determined by RIA. RESULTS: IAPP and insulin mRNA and peptide content varied widely between the tumour specimens, and there was considerable intratumour heterogeneity of peptide content. HPLC analysis indicated correct proteolytic processing of the IAPP precursor protein. Amyloid deposits were detected only in the three tumours with the highest IAPP content. In contrast to insulin, plasma levels of IAPP were not elevated in the insulinoma patients. CONCLUSIONS: The spectrum of hormone production by insulinomas cannot be inferred from only a few tissue sections due to intratumour heterogeneity. Expression of the IAPP and insulin genes is not coupled in insulinomas, which produce properly processed mature IAPP. In addition to IAPP overproduction, additional factors such as intracellular accumulation of IAPP are involved in amyloidogenesis in insulinomas.

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Takashio, S., M. Morioka, A. Fujiyama, F. Oike, S. Hanatani, H. Usuku, E. Yamamoto, K. Matsushita i K. Tsujita. "Clinical characteristics, patient selection and clinical outcomes of tafamidis treatment in transthyretin amyloidosis cardiomyopathy". European Heart Journal 43, Supplement_2 (1.10.2022). http://dx.doi.org/10.1093/eurheartj/ehac544.964.

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Abstract Background Tafamidis is a stabilizer of transthyretin, specifically designed to decrease or prevent amyloidogenesis, and improves prognosis in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). However, clinical coarse, selection of appropriate patients and monitoring therapeutic effect of tafamidis remained unclear. Purpose The aim of this study was to clarify the patients' characteristics, clinical coarse, and clinical outcomes of tafamidis in patients with ATTR-CM and to evaluate prognostic factors and changes in clinical data over time. Methods We evaluated consecutive 180 patients with ATTR-CM considering tafamids treatment. A total of 107 patients had tafamidis treatment (tafamidis treatment group) and 65 patients did not treat with tafamidis (treatment naïve group). The remaining 8 patients were preclinical. Clinical data were obtained at the consideration of tafamidis treatment. We divided the following the cut-off values of high-sensitivity cardiac troponin T (hs-cTnT); >0.05 ng/mL, B-type natriuretic peptide (BNP); >250 pg/ml, and estimated glomerular filtration rate (eGFR); <45 mL/min/1.73 m2 and calculated the score by adding 1 point if increased or decreased by more than the cut-off value. We divided patients into a low score group (0–1 point) and high score group (2–3 points). Results All of study patients in the tafamidis treatment group were wild-type ATTR-CM. Compared to tafamidis treatment group, tafamidis naïve group were significantly older (75.6±5.3 vs. 82.8±4.6 years; p<0.01), female dominant (8% vs. 28%; p<0.01), increased BNP levels (median 209 vs 306 pg/ml; p<0.01), and lower haemoglobin levels (14.1±1.8 vs. 12.4±1.8 g/dl; p<0.01). Tafamidis treatment group was significantly favourable clinical outcomes competed to treatment naïve group (p<0.05; log rank test). According to multivariate logistic regression analysis, prior heart failure hospitalization (hazard ratio [HR]: 5.93, 95% confidence interval [CI]: 1.25–28.03, p=0.03) and high score group (HR: 1.56, 95% CI: 0.37–7.25; <0.01) were the significant poor prognostic factors in tafamids treatment group. Among tafamidis treatment group, Hs-cTnT levels were significantly decreased after 12 months tafamidis treatment (0.055 [0.037–0.082] vs. 0.044 [0.033–0.077]; p<0.01) instead of no significant differences in BNP and significant decline of eGFR levels. There were no significant changes over time in the echocardiographic parameters after 12 months, and native T1 and extracellular volume fraction obtained by cardiac magnetic resonance in a limited number of patients. Conclusion The prognosis of ATTR-CM patients treated with tafamidis was favorable compared to tafamidis naïve group. Patient stratification combined with biomarkers predicted favorable prognosis in patients with tafamidis treatment. Hs-cTnT may be a useful maker for evaluating the therapeutic effect by tafamidis. Funding Acknowledgement Type of funding sources: None.

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