Dataset Information

Zn-dependent β-amyloid Aggregation and its Reversal by the Tetrapeptide HAEE.

ABSTRACT: The pathogenesis of Alzheimer's disease (AD) is associated with the formation of cerebral amyloid plaques, the main components of which are the modified Aβ molecules as well as the metal ions. Aβ isomerized at Asp7 residue (isoD7-Aβ) is the most abundant isoform in amyloid plaques. We hypothesized that the pathogenic effect of isoD7-Aβ is due to the formation of zinc-dependent oligomers, and that this interaction can be disrupted by the rationally designed tetrapeptide (HAEE). Here, we utilized surface plasmon resonance, nuclear magnetic resonance, and molecular dynamics simulation to demonstrate Zn²⁺-dependent oligomerization of isoD7-Aβ and the formation of a stable isoD7-Aβ:Zn²⁺:HAEE complex incapable of forming oligomers. To demonstrate the physiological importance of zinc-dependent isoD7-Aβ oligomerization and the ability of HAEE to interfere with this process at the organismal level, we employed transgenic nematodes overexpressing human Aβ. We show that the presence of isoD7-Aβ in the medium triggers extensive amyloidosis that occurs in a Zn²⁺-dependent manner, enhances paralysis, and shortens the animals' lifespan. Exogenous HAEE completely reverses these pathological effects of isoD7-Aβ. We conclude that the synergistic action of isoD7-Aβ and Zn²⁺ promotes Aβ aggregation and that the selected small molecules capable of interrupting this process, such as HAEE, can potentially serve as anti-amyloid therapeutics.

SUBMITTER: Mitkevich VA

PROVIDER: S-EPMC10017155 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Zn-dependent β-amyloid Aggregation and its Reversal by the Tetrapeptide HAEE.

Mitkevich Vladimir A VA Barykin Evgeny P EP Eremina Svetlana S Pani Bibhusita B Katkova-Zhukotskaya Olga O Polshakov Vladimir I VI Adzhubei Alexei A AA Kozin Sergey A SA Mironov Alexander S AS Makarov Alexander A AA Nudler Evgeny E

Aging and disease 20230401 2

The pathogenesis of Alzheimer's disease (AD) is associated with the formation of cerebral amyloid plaques, the main components of which are the modified Aβ molecules as well as the metal ions. Aβ isomerized at Asp7 residue (isoD7-Aβ) is the most abundant isoform in amyloid plaques. We hypothesized that the pathogenic effect of isoD7-Aβ is due to the formation of zinc-dependent oligomers, and that this interaction can be disrupted by the rationally designed tetrapeptide (HAEE). Here, we utilized ...[more]

PMID: 37008059

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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.

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Dataset Information

Zn-dependent β-amyloid Aggregation and its Reversal by the Tetrapeptide HAEE.

Publications

Zn-dependent β-amyloid Aggregation and its Reversal by the Tetrapeptide HAEE.

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