Zn-dependent [beta]-amyloid Aggregation and its Reversal by the Tetrapeptide HAEE
The pathogenesis of Alzheimer's disease (AD) is associated with the formation of cerebral amyloid plaques, the main components of which are the modified A[beta] molecules as well as the metal ions. A[beta] isomerized at Asp7 residue (isoD7-A[beta]) is the most abundant isoform in amyloid plaque...
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Published in | Aging and disease Vol. 14; no. 2; p. 309 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
JKL International
01.04.2023
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Subjects | |
Online Access | Get full text |
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Summary: | The pathogenesis of Alzheimer's disease (AD) is associated with the formation of cerebral amyloid plaques, the main components of which are the modified A[beta] molecules as well as the metal ions. A[beta] isomerized at Asp7 residue (isoD7-A[beta]) is the most abundant isoform in amyloid plaques. We hypothesized that the pathogenic effect of isoD7-A[beta] 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 [Zn.sup.2+]-dependent oligomerization of isoD7-A[beta] and the formation of a stable isoD7-A[beta]:[Zn.sup.2+]:HAEE complex incapable of forming oligomers. To demonstrate the physiological importance of zinc-dependent isoD7-A[beta] oligomerization and the ability of HAEE to interfere with this process at the organismal level, we employed transgenic nematodes overexpressing human A[beta]. We show that the presence of isoD7-A[beta] in the medium triggers extensive amyloidosis that occurs in a [Zn.sup.2+]-dependent manner, enhances paralysis, and shortens the animals' lifespan. Exogenous HAEE completely reverses these pathological effects of isoD7-A[beta]. We conclude that the synergistic action of isoD7-A[beta] and [Zn.sup.2+] promotes A[beta] aggregation and that the selected small molecules capable of interrupting this process, such as HAEE, can potentially serve as anti-amyloid therapeutics. Key words: Alzheimer disease, A[beta]-Peptides, Isoaspartatic acid, Zinc, Caenorhabditis elegans |
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ISSN: | 2152-5250 2152-5250 |
DOI: | 10.14336/AD.2022.0827 |