Amyloid oligomers as on-pathway precursors or off-pathway competitors of fibrils DOI Creative Commons
Martin Muschol, Wolfgang Hoyer

Frontiers in Molecular Biosciences, Journal Year: 2023, Volume and Issue: 10

Published: Feb. 9, 2023

Amyloid Diseases involve the growth of disease specific proteins into amyloid fibrils and their deposition in protein plaques. fibril formation is typically preceded by oligomeric intermediates. Despite significant efforts, role or oligomers play etiology any given remains controversial. In neurodegenerative disease, though, are widely considered critical contributors to symptoms. Aside from as inevitable on-pathway precursors formation, there evidence for off-pathway oligomer competing with growth. The distinct mechanisms pathways directly affect our understanding under which conditions emerge vivo, whether coupled to, from, formation. this review, we will discuss basic energy landscapes underlying vs. oligomers, relation related aggregation kinetics, resulting implications etiology. We review on how differences local environment assembly can dramatically shift relative preponderance fibrils. Finally, comment gaps knowledge assembly, structure, assess relevance

Language: Английский

A new era for understanding amyloid structures and disease DOI
M.G. Iadanza, Matthew P. Jackson, Eric W. Hewitt

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2018, Volume and Issue: 19(12), P. 755 - 773

Published: Sept. 20, 2018

Language: Английский

Citations

869
The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade DOI Creative Commons
Erika N. Cline, Maíra A. Bicca, Kirsten L. Viola

et al.

Journal of Alzheimer s Disease, Journal Year: 2018, Volume and Issue: 64(s1), P. S567 - S610

Published: June 12, 2018

The amyloid-␤ oligomer (A␤O) hypothesis was introduced in 1998.It proposed that the brain damage leading to Alzheimer's disease (AD) instigated by soluble, ligand-like A␤Os.This based on discovery fibril-free synthetic preparations of A␤Os were potent CNS neurotoxins rapidly inhibited long-term potentiation and, with time, caused selective nerve cell death (Lambert et al., 1998).The mechanism attributed disrupted signaling involving tyrosine-protein kinase Fyn, mediated an unknown toxin receptor.Over 4,000 articles concerning have been published since then, including more than 400 reviews.A␤Os shown accumulate AD-dependent manner human and animal model tissue experimentally, impair learning memory instigate major facets AD neuropathology, tau pathology, synapse deterioration loss, inflammation, oxidative damage.As reviewed Hayden Teplow 2013, A␤O "has all but supplanted amyloid cascade."Despite emerging understanding role played pathogenesis, not yet received clinical attention given plaques, which at core attempts therapeutics diagnostics are no longer regarded as most pathogenic form A␤.However, if momentum research continues, particularly efforts elucidate key aspects structure, a clear path successful modifying therapy can be envisioned.Ensuring lessons learned from recent, late-stage failures applied appropriately throughout therapeutic development will further enable likelihood near-term.

Language: Английский

Citations

717
Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis DOI
Phuong H. Nguyen, Ayyalusamy Ramamoorthy, Bikash R. Sahoo

et al.

Chemical Reviews, Journal Year: 2021, Volume and Issue: 121(4), P. 2545 - 2647

Published: Feb. 5, 2021

Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural dynamic characterization all species along pathways from monomers to fibrils challenging by experimental computational means because they involve intrinsically disordered proteins most diseases. Yet understanding how amyloid become toxic challenge developing treatment for these Here we review what computer, vitro, vivo, pharmacological experiments tell us about accumulation deposition oligomers (Aβ, tau), α-synuclein, IAPP, superoxide dismutase 1 proteins, which have been mainstream concept underlying Alzheimer's disease (AD), Parkinson's (PD), type II diabetes (T2D), amyotrophic lateral sclerosis (ALS) research, respectively, years.

Language: Английский

Citations

552
Peptide-Based Vaccines: Current Progress and Future Challenges DOI Open Access
Ryan J. Malonis, Jonathan R. Lai,

Olivia Vergnolle

et al.

Chemical Reviews, Journal Year: 2019, Volume and Issue: 120(6), P. 3210 - 3229

Published: Dec. 5, 2019

Vaccines have had a profound impact on the management and prevention of infectious disease. In addition, development vaccines against chronic diseases has attracted considerable interest as an approach to prevent, rather than treat, conditions such cancer, Alzheimer's disease, others. Subunit consist nongenetic components agent or disease-related epitope. this Review, we discuss peptide-based their potential in three therapeutic areas: cancer. We factors that contribute vaccine efficacy how these parameters may potentially be modulated by design. examine both clinically tested well nascent approaches explore current challenges remedies. While peptide hold substantial promise human many obstacles remain hampered clinical use; thus, continued research efforts address are warranted.

Language: Английский

Citations

508
Amyloid-β and tau complexity — towards improved biomarkers and targeted therapies DOI
Juan Carlos Polanco, Chuanzhou Li, Liviu‐Gabriel Bodea

et al.

Nature Reviews Neurology, Journal Year: 2017, Volume and Issue: 14(1), P. 22 - 39

Published: Dec. 15, 2017

Language: Английский

Citations

351
Folding and Misfolding of Human Membrane Proteins in Health and Disease: From Single Molecules to Cellular Proteostasis DOI Creative Commons
Justin T. Marinko, Hui Huang, Wesley D. Penn

et al.

Chemical Reviews, Journal Year: 2019, Volume and Issue: 119(9), P. 5537 - 5606

Published: Jan. 4, 2019

Advances over the past 25 years have revealed much about how structural properties of membranes and associated proteins are linked to thermodynamics kinetics membrane protein (MP) folding. At same time biochemical progress has outlined cellular proteostasis networks mediate MP folding manage misfolding in cell. When combined with results from genomic sequencing, these studies established paradigms for molecular etiologies a variety diseases. This emerging framework paved way development new class small molecule “pharmacological chaperones” that bind stabilize misfolded variants, some which now clinical use. In this review, we comprehensively outline current perspectives on integral MPs as well mechanisms quality control. Based perspectives, highlight opportunities innovations bridge our understanding energetics nuanced complexity biological systems. Given many linkages between human disease, also examine exciting leverage advances address challenges therapeutics precision medicine.

Language: Английский

Citations

228
Aβ(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage DOI Creative Commons
Sonia Ciudad, Eduard Puig, Thomas Botzanowski

et al.

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: June 15, 2020

Abstract Formation of amyloid-beta (Aβ) oligomer pores in the membrane neurons has been proposed to explain neurotoxicity Alzheimerʼs disease (AD). Here, we present three-dimensional structure an Aβ formed a mimicking environment, namely Aβ(1-42) tetramer, which comprises six stranded β-sheet core. The two faces core are hydrophobic and surrounded by membrane-mimicking environment while edges hydrophilic solvent-exposed. By increasing concentration sample, octamers also formed, made tetramers facing each other forming β-sandwich structure. Notably, inserted into lipid bilayers as well-defined pores. To establish structure-membrane activity relationships, molecular dynamics simulations were carried out. These studies revealed mechanism disruption water permeation occurred through lipid-stabilized mediated residues located on β-sheets oligomers.

Language: Английский

Citations

205
Ion Channel Formation by Amyloid-β42 Oligomers but Not Amyloid-β40 in Cellular Membranes DOI Creative Commons
David Bode, Mark D. Baker, John H. Viles

et al.

Journal of Biological Chemistry, Journal Year: 2016, Volume and Issue: 292(4), P. 1404 - 1413

Published: Dec. 8, 2016

A central hallmark of Alzheimer's disease is the presence extracellular amyloid plaques chiefly consisting amyloid-β (Aβ) peptides in brain interstitium. Aβ largely exists two isoforms, 40 and 42 amino acids long, but a large body evidence points to Aβ(1-42) rather than Aβ(1-40) as cytotoxic form. One proposed mechanism by which exerts toxicity formation ion channel pores that disrupt intracellular Ca2+ homeostasis. However, previous studies using membrane mimetics have not identified any notable difference forming properties between Aβ(1-42). Here, we tested whether more physiological environment, membranes excised from HEK293 cells neuronal origin, would reveal differences relative ability monomeric, oligomeric, fibrillar forms both preparations were characterized with transmission electron microscopy thioflavin T fluorescence. was then exposed face membranes, transmembrane currents monitored patch clamp. Our data indicated assemblies oligomeric form voltage-independent, non-selective channels. In contrast, oligomers, fibers, monomers did Ion conductance results suggested formed three distinct pore structures 1.7-, 2.1-, 2.4-nm diameters. findings demonstrate only contains unique structural features facilitate insertion formation, now aligning differential neurotoxic effect disease.

Language: Английский

Citations

183
Effects ofin vivoconditions on amyloid aggregation DOI
Michael C. Owen, David Gnutt,

Mimi Gao

et al.

Chemical Society Reviews, Journal Year: 2019, Volume and Issue: 48(14), P. 3946 - 3996

Published: Jan. 1, 2019

One of the grand challenges biophysical chemistry is to understand principles that govern protein misfolding and aggregation, which a highly complex process sensitive initial conditions, operates on huge range length- timescales, has products from dimers macroscopic amyloid fibrils. Aberrant aggregation associated with more than 25 diseases, include Alzheimer's, Parkinson's, Huntington's, type II diabetes. Amyloid been extensively studied in test tube, therefore under conditions are far physiological relevance. Hence, there dire need extend these investigations vivo where formation affected by myriad biochemical interactions. As hallmark neurodegenerative interactions be understood detail develop novel therapeutic interventions, as millions people globally suffer disorders The aim this review document progress research physicochemical perspective special focus factors influencing amyloid-β peptide, islet polypeptide, α-synuclein, hungingtin protein.

Language: Английский

Citations

171
Misfolded protein oligomers: mechanisms of formation, cytotoxic effects, and pharmacological approaches against protein misfolding diseases DOI Creative Commons
Dillon J. Rinauro, Fabrizio Chiti, Michele Vendruscolo

et al.

Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)

Published: Feb. 20, 2024

The conversion of native peptides and proteins into amyloid aggregates is a hallmark over 50 human disorders, including Alzheimer's Parkinson's diseases. Increasing evidence implicates misfolded protein oligomers produced during the formation process as primary cytotoxic agents in many these devastating conditions. In this review, we analyze processes by which are formed, their structures, physicochemical properties, population dynamics, mechanisms cytotoxicity. We then focus on drug discovery strategies that target ability to disrupt cell physiology trigger degenerative processes.

Language: Английский

Citations

51