Dataset Information

Amyloid-?(1-42) Aggregation Initiates Its Cellular Uptake and Cytotoxicity.

ABSTRACT: The accumulation of amyloid ? peptide(1-42) (A?(1-42)) in extracellular plaques is one of the pathological hallmarks of Alzheimer disease (AD). Several studies have suggested that cellular reuptake of A?(1-42) may be a crucial step in its cytotoxicity, but the uptake mechanism is not yet understood. A? may be present in an aggregated form prior to cellular uptake. Alternatively, monomeric peptide may enter the endocytic pathway and conditions in the endocytic compartments may induce the aggregation process. Our study aims to answer the question whether aggregate formation is a prerequisite or a consequence of A? endocytosis. We visualized aggregate formation of fluorescently labeled A?(1-42) and tracked its internalization by human neuroblastoma cells and neurons. ?-Sheet-rich A?(1-42) aggregates entered the cells at low nanomolar concentration of A?(1-42). In contrast, monomer uptake faced a concentration threshold and occurred only at concentrations and time scales that allowed A?(1-42) aggregates to form. By uncoupling membrane binding from internalization, we found that A?(1-42) monomers bound rapidly to the plasma membrane and formed aggregates there. These structures were subsequently taken up and accumulated in endocytic vesicles. This process correlated with metabolic inhibition. Our data therefore imply that the formation of ?-sheet-rich aggregates is a prerequisite for A?(1-42) uptake and cytotoxicity.

SUBMITTER: Jin S

PROVIDER: S-EPMC5016693 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Amyloid-β(1-42) Aggregation Initiates Its Cellular Uptake and Cytotoxicity.

Jin Sha S Kedia Niraja N Illes-Toth Eva E Haralampiev Ivan I Prisner Simon S Herrmann Andreas A Wanker Erich E EE Bieschke Jan J

The Journal of biological chemistry 20160725 37

The accumulation of amyloid β peptide(1-42) (Aβ(1-42)) in extracellular plaques is one of the pathological hallmarks of Alzheimer disease (AD). Several studies have suggested that cellular reuptake of Aβ(1-42) may be a crucial step in its cytotoxicity, but the uptake mechanism is not yet understood. Aβ may be present in an aggregated form prior to cellular uptake. Alternatively, monomeric peptide may enter the endocytic pathway and conditions in the endocytic compartments may induce the aggregat ...[more]

PMID: 27458018

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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

Amyloid-?(1-42) Aggregation Initiates Its Cellular Uptake and Cytotoxicity.

Publications

Amyloid-β(1-42) Aggregation Initiates Its Cellular Uptake and Cytotoxicity.

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