Thin‐Plate Superstructures of the Immunogenic 33‐mer Gliadin Peptide

ChemBioChem, Год журнала: 2022, Номер 23(22)

Опубликована: Сен. 26, 2022

Gluten related-disorders have a prevalence of 1-5 % worldwide triggered by the ingestion gluten proteins in wheat, rye, barley, and some oats. In wheat gluten, most studied protein is gliadin, whose immunodominant 33-mer amino acid fragment remains after digestive proteolysis accumulates gut mucosa. Here, we report formation thin-plate superstructures using intrinsic tyrosine (Tyr) steady-state fluorescence anisotropy cryo-TEM combination with water tension measurements. Furthermore, showed that decay measurements fluorophore Tyr provided information on early stages structures. Finally, conformational analysis residues minimalist models molecular dynamic simulations (MD) demonstrated changes rotamer states depend oligomerization stage. Our findings further advance understanding gliadin peptide their relation to health disease.

Язык: Английский

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The contribution of oligodendrocytes to amyloid and tau pathologies in mouse models of Alzheimer’s disease

Опубликована: Янв. 1, 2024

Oligodendrocytes (OLs) are the myelinating glia of CNS and capable metabolically supporting long axonal projections by providing local fuel production. OL myelin health, however, start degrading around second half human life, which coincides with predicted age at Alzheimer's disease (AD), a debilitating neurodegenerative disease, may begin to develop. Although AD is often considered gray matter, or neurons be exact, recent evidence has indicated involvement glial cells in its pathophysiology. Earlier work shown that dysfunctional risk factor for amyloid-β (Aβ) plaque burden, one hallmarks AD. Thus, general aim this thesis expand our current understanding role context In Chapter I, we investigated whether OLs, alongside excitatory (ExNs), can generate Aβ vivo. We first generated genetically modified mouse models amyloidosis cell-type specific ablation β-secretase 1 (BACE1), key enzyme By combining quantitative light-sheet microscopy (LSM), 2D imaging, vitro cultures, sensitive electrochemiluminescence assay, report novel data showing OLs contribute burden vivo, especially white matter regions where predominate. ExNs, remain primary contributor Interestingly, genetic deletion BACE1 cortical hippocampal ExNs resulted major reductions subcortical burden. This suggests processing occur fibers originating from forebrain projecting into structures, would then released. analyzing several chapter, propose deposition requires reaching threshold concentration, without ExN contribution, concentration initially insufficient induce seeding. Together, findings chapter potentially advance knowledge on seeding growth kinetics, further allow us consider as viable target anti-amyloid therapies such inhibitors. The objective II was previous study linking amyloid pathology turning focus tau pathology. precedes tau, still known executioner neuronal cell death performed imaging battery behavioral tests model tauopathy, inducing acute dysmyelination separate cohorts. discovered damage heightened both experimental cases, stronger effect seen due dysmyelination. Worsening also correlated outcomes: Mice were much slower than control animal, experienced additive motor impairments evident anxiety reduction defects cognitive processing. sum, preliminarily suggest leads worsen Finally, III, potential cause large discrepancies utilizing LSM labeled hemibrains 5xFAD mice, observed transgenic inheritance pattern modulated load after age- sex-matching. inherited their transgenes paternal source developed significantly greater maternal counterparts. previously unreported unlikely result immune priming instead, likely epigenetic modulation transgene itself. Our could thus support conduct more reproducible experiments field animal research. conclusion, indicates serve contributory roles thought, terms pathologies. missing link production accumulation, opening up new avenues research pathophysiology development strategies address pathogenesis.

Язык: Английский

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Interactions of Amyloid Fibrils with Functional Proteins: Modulating Effect of Polyphenols

East European Journal of Physics, Год журнала: 2024, Номер 2, С. 463 - 469

Опубликована: Июнь 1, 2024

The elucidation of interactions between functional proteins and amyloid fibrils is crucial for understanding the molecular basis diseases, which are characterized by protein misfolding aggregation. Polyphenols, due to their diverse biological properties, have garnered attention potential modulate these protein-fibril interactions, thereby influencing disease progression offering therapeutic possibilities. In this study, we investigated effects quercetin its binary combinations with other polyphenols on binding affinity cytochrome c, in both reduced oxidized forms, insulin apolipoprotein A-I. Our results demonstrate that complexation c decreases forms protein, while increasing A-I fibrils. This modulation was attributed competitive or allosteric exerted c. Additionally, did not reduce they decrease case counterpart. These findings highlight selective significant impact polyphenolic compounds proteins, suggesting pathways intervention amyloid-related disorders.

Язык: Английский

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Early divergent modulation of NLRP2′s and NLRP3′s inflammasome sensors vs. AIM2′s one by signals from Aβ•Calcium-sensing receptor complexes in human astrocytes

Brain Research, Год журнала: 2024, Номер 1846, С. 149283 - 149283

Опубликована: Окт. 18, 2024

Язык: Английский

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Detrimental effects of soluble α-synuclein oligomers at excitatory glutamatergic synapses

Frontiers in Aging Neuroscience, Год журнала: 2023, Номер 15

Опубликована: Март 16, 2023

Introduction Oligomeric and fibrillar species of the synaptic protein α-synuclein are established key players in pathophysiology Parkinson’s disease other synucleinopathies. Increasing evidence literature points to prefibrillar oligomers as main cytotoxic driving dysfunction diverse neurotransmitter systems even at early stages. Of note, soluble have recently been shown alter plasticity mechanisms glutamatergic cortico-striatal synapse. However, molecular morphological detrimental events triggered by aggregates that ultimately lead excitatory failure remain mostly elusive. Methods In present study, we aimed clarify effects (sOligo) synucleinopathies hippocampal synapses. To investigate defects striatal synapse vivo , sOligo were inoculated dorsolateral striatum 2-month-old wild-type C57BL/6J mice, analyses conducted 42 84 days post-injection. parallel, primary cultures rat neurons exposed sOligo, performed after 7 treatment. Results injection impaired post-synaptic retention ionotropic glutamate receptors decreased levels phosphorylated ERK These not correlated with alterations dendritic spines. Conversely, chronic vitro administration caused a significant decrease phosphorylation but did significantly or spine density neurons. Conclusion Overall, our data indicate involved pathogenic changes synapse, confirming effect these an synucleinopathy model. Moreover, affects signaling pathway similarly neurons, possibly representing mechanism anticipates loss.

Язык: Английский

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