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Free Gangliosides Can Alter Amyloid-β Aggregation.

ABSTRACT: A recently proposed lipid-chaperone hypothesis suggests that free lipid molecules, not bound to membranes, affect the aggregation of amyloidogenic peptides such as amyloid-β (Aβ) peptides, whose aggregates are the hallmarks of Alzheimer's disease. Here, we combine experiments with all-atom molecular dynamics simulations in explicit solvent to explore the effects of neuronal ganglioside GM1, abundant in mammalian brains, on the aggregation of two principal isoforms of Aβ, Aβ40 and Aβ42. Our simulations show that free GM1 forms stable, highly water-soluble complexes with both isoforms, and nuclear magnetic resonance experiments support the formation of well-ordered, structurally compact GM1+Aβ complexes. By simulation, we also show that Aβ40 monomers display a preference for binding to GM1-containing hetero-oligomers over GM1-lacking homo-oligomers, while Aβ42 monomers have the opposite preference. These observations explain why GM1 dose-dependently inhibits Aβ40 aggregation but has no effect on Aβ42 aggregation, as assessed by thioflavin T fluorescence.

SUBMITTER: Chakravorty A

PROVIDER: S-EPMC9700483 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Free Gangliosides Can Alter Amyloid-β Aggregation.

Chakravorty Arghya A McCalpin Samuel D SD Sahoo Bikash R BR Ramamoorthy Ayyalusamy A Brooks Charles L CL

The journal of physical chemistry letters 20220929 40

A recently proposed lipid-chaperone hypothesis suggests that free lipid molecules, not bound to membranes, affect the aggregation of amyloidogenic peptides such as amyloid-β (Aβ) peptides, whose aggregates are the hallmarks of Alzheimer's disease. Here, we combine experiments with all-atom molecular dynamics simulations in explicit solvent to explore the effects of neuronal ganglioside GM1, abundant in mammalian brains, on the aggregation of two principal isoforms of Aβ, Aβ40 and Aβ42. Our simul ...[more]

PMID: 36174129

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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-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.

Dataset Information

Free Gangliosides Can Alter Amyloid-β Aggregation.

Publications

Free Gangliosides Can Alter Amyloid-β Aggregation.

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