Age-Dependent Protein Aggregation Initiates Amyloid-β Aggregation
نویسندگان
چکیده
Aging is the most important risk factor for neurodegenerative diseases associated with pathological protein aggregation such as Alzheimer's disease. Although aging is an important player, it remains unknown which molecular changes are relevant for disease initiation. Recently, it has become apparent that widespread protein aggregation is a common feature of aging. Indeed, several studies demonstrate that 100s of proteins become highly insoluble with age, in the absence of obvious disease processes. Yet it remains unclear how these misfolded proteins aggregating with age affect neurodegenerative diseases. Importantly, several of these aggregation-prone proteins are found as minor components in disease-associated hallmark aggregates such as amyloid-β plaques or neurofibrillary tangles. This co-localization raises the possibility that age-dependent protein aggregation directly contributes to pathological aggregation. Here, we show for the first time that highly insoluble proteins from aged Caenorhabditis elegans or aged mouse brains, but not from young individuals, can initiate amyloid-β aggregation in vitro. We tested the seeding potential at four different ages across the adult lifespan of C. elegans. Significantly, protein aggregates formed during the early stages of aging did not act as seeds for amyloid-β aggregation. Instead, we found that changes in protein aggregation occurring during middle-age initiated amyloid-β aggregation. Mass spectrometry analysis revealed several late-aggregating proteins that were previously identified as minor components of amyloid-β plaques and neurofibrillary tangles such as 14-3-3, Ubiquitin-like modifier-activating enzyme 1 and Lamin A/C, highlighting these as strong candidates for cross-seeding. Overall, we demonstrate that widespread protein misfolding and aggregation with age could be critical for the initiation of pathogenesis, and thus should be targeted by therapeutic strategies to alleviate neurodegenerative diseases.
منابع مشابه
Molecular Dynamics and Molecular Docking Studies on the Interaction between Four Tetrahydroxy Derivatives of Polyphenyls and Beta Amyloid
Interactions of 3,3',4,4'-tetrahydroxybiphenyl (BPT) and three isomeric 3,3",4,4"-tetrahydroxyterphenyls (OTT, MTT, PTT) with Alzheimer’s amyloid-β peptide (Aβ) were studied by molecular dynamics simulation and molecular docking. Structural parameters such as Root-mean-square derivations (RMSD), radial distribution function (RDF), helix percentage and other physical parameters were obtained. Th...
متن کاملSynthesis and biological assessment of 2-hydroxyiminoethanones as anti-inflammatory and β-amyloid aggregation inhibitors
Alzheimer’s disease (AD) is a neuroinflammatory based pathologic state in which β-amyloid aggregates are a major devastating agents. In this study, a series of 2-hydroxyiminoethanones were synthesized and evaluated as anti-inflammatory in carrageenan and formalin tests and inhibitors of β-amyloid aggregation. Compounds 1-10b were synthesized through a two-step reaction. Results: Compounds 1-5b ...
متن کاملSynthesis and biological assessment of 2-hydroxyiminoethanones as anti-inflammatory and β-amyloid aggregation inhibitors
Alzheimer’s disease (AD) is a neuroinflammatory based pathologic state in which β-amyloid aggregates are a major devastating agents. In this study, a series of 2-hydroxyiminoethanones were synthesized and evaluated as anti-inflammatory in carrageenan and formalin tests and inhibitors of β-amyloid aggregation. Compounds 1-10b were synthesized through a two-step reaction. Results: Compounds 1-5b ...
متن کاملPreparation and study of the inhibitory effect of nano-niosomes containing essential oil from artemisia absinthium on amyloid fibril formation
Objective(s): Artemisia absinthium is an aromatic, perennial small shrub that shows multiple medical benefits, including anticancerous, neuroprotective, antifungal, hepatoprotective, antidepressant and antioxidant properties. One of the effective approaches to treat Alzheimer’s disease is targeting amyloid aggregation by antiamyloid drugs. In the current research study, an excellent grouping of...
متن کاملInhibition of Amyloid Fibrils Formation from Hen Egg White Lysozyme by Satureia Hortensis Extract and its Effect on Learning and Spatial Memory of Rats
Background & Aims: Alzheimer's disease is a neurodegenerative disorder characterized by the abnormal aggregation of amyloid-β plaques in the brain. Although several studies have been done for finding effective medicines in the treatment of this disease, a drug that inhibits amyloid β aggregation and ameliorates the disorder has not been approved so far. One important therapeutic approach is use...
متن کامل