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Charge dependent retardation of amyloid ? aggregation by hydrophilic proteins.

ABSTRACT: The aggregation of amyloid ? peptides (A?) into amyloid fibrils is implicated in the pathology of Alzheimer's disease. In light of the increasing number of proteins reported to retard A? fibril formation, we investigated the influence of small hydrophilic model proteins of different charge on A? aggregation kinetics and their interaction with A?. We followed the amyloid fibril formation of A?40 and A?42 using thioflavin T fluorescence in the presence of six charge variants of calbindin D9k and single-chain monellin. The formation of fibrils was verified with transmission electron microscopy. We observe retardation of the aggregation process from proteins with net charge +8, +2, -2, and -4, whereas no effect is observed for proteins with net charge of -6 and -8. The single-chain monellin mutant with the highest net charge, scMN+8, has the largest retarding effect on the amyloid fibril formation process, which is noticeably delayed at as low as a 0.01:1 scMN+8 to A?40 molar ratio. scMN+8 is also the mutant with the fastest association to A?40 as detected by surface plasmon resonance, although all retarding variants of calbindin D9k and single-chain monellin bind to A?40.

SUBMITTER: Assarsson A

PROVIDER: S-EPMC3990944 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Charge dependent retardation of amyloid β aggregation by hydrophilic proteins.

Assarsson Anna A Hellstrand Erik E Cabaleiro-Lago Celia C Linse Sara S

ACS chemical neuroscience 20140206 4

The aggregation of amyloid β peptides (Aβ) into amyloid fibrils is implicated in the pathology of Alzheimer's disease. In light of the increasing number of proteins reported to retard Aβ fibril formation, we investigated the influence of small hydrophilic model proteins of different charge on Aβ aggregation kinetics and their interaction with Aβ. We followed the amyloid fibril formation of Aβ40 and Aβ42 using thioflavin T fluorescence in the presence of six charge variants of calbindin D9k and s ...[more]

PMID: 24475785

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Project description: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-? 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-? 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-? aggregation. Instead, we found that changes in protein aggregation occurring during middle-age initiated amyloid-? aggregation. Mass spectrometry analysis revealed several late-aggregating proteins that were previously identified as minor components of amyloid-? 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.

Dataset Information

Charge dependent retardation of amyloid ? aggregation by hydrophilic proteins.

Publications

Charge dependent retardation of amyloid β aggregation by hydrophilic proteins.

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