Solving the Amyloid Paradox: Unveiling the Complex Pathogenicity of Amyloid Fibrils DOI Creative Commons
Maksim I. Sulatsky, Olesya V. Stepanenko, Olga V. Stepanenko

и другие.

Aggregate, Год журнала: 2025, Номер unknown

Опубликована: Июнь 4, 2025

ABSTRACT More than a century ago, it was known that the accumulation of ordered protein aggregates, amyloid fibrils, accompanies several serious and still largely incurable pathologies, including Alzheimer's Parkinson's diseases. The striking gap between decades research identifying amyloids as one key drivers neurodegeneration persistent lack effective anti‐amyloid therapies reveals perplexing contradiction, which we define “amyloid paradox.” To address this paradox, here summarize analyze current perspectives on unique properties pathogenic mechanisms amyloids, highlighting variability complexity their biological consequences uncovering risks limitations encountered in combating these aggregates. We conceptualize fibril pathogenicity complex cascade extending well beyond direct cytotoxicity, such arising from disruption membranes other cellular organelles. This review encompasses amyloids' disruptive effects processes ability to trigger inflammatory responses, resistance degradation, capacity regenerate after apparent destruction, tendency propagate throughout organism, propensity cytotoxicity‐increasing transformation, sequester pathologically modify essential biomolecules. integrated analysis why single‐target therapeutic approaches often fail suggests strategies must multiple aspects simultaneously. conceptual reframing threats fibrils helps explain origins enhances our understanding agents, provides foundation for developing more safe neurodegenerative These should interconnected nature rather its targeting isolated aspects.

Язык: Английский

Sub-nanosecond dynamics of phospholipid membranes interacting with polymorphic amyloid fibrils observed by elastic incoherent neutron scattering DOI
Tatsuhito Matsuo, Agathe Bélime, Francesca Natali

и другие.

Physical Chemistry Chemical Physics, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Amyloidosis such as Alzheimer's or Parkinson's disease is characterized by deposition of amyloid fibrils in the brain various internal organs. The onset amyloidosis related to strength cytotoxicity caused toxic species. In addition, show a polymorphism, i.e., some types are more cytotoxic than others. It thus important elucidate molecular mechanism cytotoxicity, which ultimately interactions between and cell membranes. this study, modulation dynamics phospholipid membranes induced binding polymorphic with different levels was studied elastic incoherent neutron scattering temperature range 280 K 310 K. were formed model system hen egg white lysozyme at pH 2.7 6.0 vesicles DMPG DMPC. curves analyzed terms mean square positional fluctuations (MSPF) atomic motions, including its distribution, function temperature, flexibility. major findings are: (1) Both less decreased flexibility DMPG. (2) While DMPC, increased it. (3) Close physiological body larger MSPFs both phospholipids an enhanced motional heterogeneity. These results imply that associated stronger cytotoxicity.

Язык: Английский

Процитировано

0
Cytotoxicity of Amyloid β1–42 Fibrils to Brain Immune Cells DOI Creative Commons

Mikhail Matveyenka,

М. В. Шолух,

Dmitry Kurouski

и другие.

ACS Chemical Neuroscience, Год журнала: 2025, Номер unknown

Опубликована: Март 8, 2025

Alzheimer's disease (AD) is a progressive pathology that linked to abrupt aggregation of amyloid β1–42 (Aβ1–42) peptide in the central nervous system. Aβ1–42 yields oligomers and fibrils, toxic protein aggregates cause neuronal degeneration frontal lobe brain. Although neurons remain focus AD for decades, growing body evidence suggests immune cells brain can be major AD. However, extent which are classes remains unclear. In current study, we examine cytotoxic effects fibrils on macrophages, dendritic cells, microglia. These play vitally important roles development homeostasis We found caused calcium release enhanced levels reactive oxygen species microglia as well neurons. also investigated lysozymes these could alter properties Aβ1–42. Our results showed lysosomes extracted from drastically accelerated altered cytotoxicity aggregates. indicate impairment critically aspect neurodegenerative processes taking place upon onset

Язык: Английский

Процитировано

0
Selective activation of antioxidant resources and energy deficiency in Marinesco–Sjögren syndrome fibroblasts as an adaptive biological response to Sil1 loss DOI Creative Commons

Valeria Panella,

Francesca Potenza,

Carla Tatone

и другие.

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Апрель 11, 2025

Язык: Английский

Процитировано

0
The role of phospholipid saturation and composition in α‐synuclein aggregation and toxicity: A dual in vitro and in vivo approach DOI
Aidan P. Holman, Tianyi Dou,

Mikhail Matveyenka

и другие.

Protein Science, Год журнала: 2025, Номер 34(5)

Опубликована: Апрель 18, 2025

Abstract Parkinson's disease is characterized by a progressive accumulation of α‐synuclein (α‐syn) aggregates in Lewy bodies, extracellular deposits found the midbrain, hypothalamus, and thalamus. The rate α‐syn aggregation, as well secondary structure oligomers fibrils, can be uniquely altered lipids. However, role saturation fatty acids (FAs) such lipids aggregation properties remains unclear. In this study, we investigated effect FAs phosphatidylcholine (PC) cardiolipin (CL), mixture these phospholipids on aggregation. We that although plays very little if any protein morphology aggregates, it determined fibrils. Furthermore, formed presence both saturated unsaturated PC CL, mixtures phospholipids, exert significantly higher cell toxicity compared to lipid‐free environment. To extend findings, conducted vivo studies using C. elegans , where assessed lipid‐modified organismal survival neurotoxicity. Our results suggest present plasma mitochondrial membranes key determinant and, consequently, These findings provide new insights into pathogenesis highlight potential targets for therapeutic intervention.

Язык: Английский

Процитировано

0
Solving the Amyloid Paradox: Unveiling the Complex Pathogenicity of Amyloid Fibrils DOI Creative Commons
Maksim I. Sulatsky, Olesya V. Stepanenko, Olga V. Stepanenko

и другие.

Aggregate, Год журнала: 2025, Номер unknown

Опубликована: Июнь 4, 2025

ABSTRACT More than a century ago, it was known that the accumulation of ordered protein aggregates, amyloid fibrils, accompanies several serious and still largely incurable pathologies, including Alzheimer's Parkinson's diseases. The striking gap between decades research identifying amyloids as one key drivers neurodegeneration persistent lack effective anti‐amyloid therapies reveals perplexing contradiction, which we define “amyloid paradox.” To address this paradox, here summarize analyze current perspectives on unique properties pathogenic mechanisms amyloids, highlighting variability complexity their biological consequences uncovering risks limitations encountered in combating these aggregates. We conceptualize fibril pathogenicity complex cascade extending well beyond direct cytotoxicity, such arising from disruption membranes other cellular organelles. This review encompasses amyloids' disruptive effects processes ability to trigger inflammatory responses, resistance degradation, capacity regenerate after apparent destruction, tendency propagate throughout organism, propensity cytotoxicity‐increasing transformation, sequester pathologically modify essential biomolecules. integrated analysis why single‐target therapeutic approaches often fail suggests strategies must multiple aspects simultaneously. conceptual reframing threats fibrils helps explain origins enhances our understanding agents, provides foundation for developing more safe neurodegenerative These should interconnected nature rather its targeting isolated aspects.

Язык: Английский

Процитировано

0