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Big dynorphin is a neuroprotector scaffold against amyloid β-peptide aggregation and cell toxicity.

ABSTRACT: Amyloid β-peptide (Aβ) misfolding into β-sheet structures triggers neurotoxicity inducing Alzheimer's disease (AD). Molecules able to reduce or to impair Aβ aggregation are highly relevant as possible AD treatments since they should protect against Aβ neurotoxicity. We have studied the effects of the interaction of dynorphins, a family of opioid neuropeptides, with Aβ₄₀ the most abundant species of Aβ. Biophysical measurements indicate that Aβ₄₀ interacts with Big Dynorphin (BigDyn), lowering the amount of hydrophobic aggregates, and slowing down the aggregation kinetics. As expected, we found that BigDyn protects against Aβ₄₀ aggregates when studied in human neuroblastoma cells by cell survival assays. The cross-interaction between BigDyn and Aβ₄₀ provides insight into the mechanism of amyloid pathophysiology and may open up new therapy possibilities.

SUBMITTER: Gallego-Villarejo L

PROVIDER: S-EPMC9582793 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Big dynorphin is a neuroprotector scaffold against amyloid β-peptide aggregation and cell toxicity.

Gallego-Villarejo Lucía L Wallin Cecilia C Król Sylwia S Enrich-Bengoa Jennifer J Suades Albert A Aguilella-Arzo Marcel M Gomara María José MJ Haro Isabel I Wärmlander Sebastian S Muñoz Francisco J FJ Gräslund Astrid A Perálvarez-Marín Alex A

Computational and structural biotechnology journal 20221014

Amyloid β-peptide (Aβ) misfolding into β-sheet structures triggers neurotoxicity inducing Alzheimer's disease (AD). Molecules able to reduce or to impair Aβ aggregation are highly relevant as possible AD treatments since they should protect against Aβ neurotoxicity. We have studied the effects of the interaction of dynorphins, a family of opioid neuropeptides, with Aβ<sub>40</sub> the most abundant species of Aβ. Biophysical measurements indicate that Aβ<sub>40</sub> interacts with Big Dynorphin ...[more]

PMID: 36284704

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Project description:MiRNA molecules are important post-transcriptional regulators of gene expression in the brain function. Altered miRNA profiles could represent a defensive response against the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease (AD). Endogenous miRNAs have lower toxic effects than other gene silencing methods, thus enhancing the expression of defensive miRNA could be an effective therapy. However, little is known about the potential of targeting miRNAs for the treatment of AD. Here, we examined the function of the miR-200 family (miR-200a, -141, -429, -200b, -200c), identified using miRNA microarray analysis of cortical tissue from Tg2576 transgenic mice. In murine primary neurons, we found that upregulation of miR-200b or -200c was induced by the addition of amyloid beta (Aβ). Neurons transfected with miR-200b or -200c reduced secretion of Aβ in conditioned medium. Moreover, mice infused with miR-200b/c into the brain were relieved of memory impairments induced by intracerebroventricular injection of oligomeric Aβ, and demonstrated proper spatial learning in the Barnes maze. To gain further understanding of the relationship between miR-200b/c and Aβ, we identified target mRNAs via an RNA-binding protein immunoprecipitation-microarray assay. Western blot analysis showed that expression of ribosomal protein S6 kinase B1 (S6K1), a candidate target, was inhibited by miR-200c. S6K1, a downstream effector of mammalian target of rapamycin (mTOR), serves as a negative feedback mediator that phosphorylates insulin receptor substrate 1 at serine residues (IRS-1pSer). S6K1-dependent IRS-1pSer suppresses insulin signaling leading to insulin resistance, which is frequently observed in AD brains. Notably, miR-200b/c transfection of SH-SY5Y cells reduced the levels of IRS-1pSer. This finding indicates that miR-200b/c has the potential to alleviate insulin resistance via modulation of S6K1. Taken together, miR-200b/c may contribute to reduce Aβ secretion and Aβ-induced cognitive impairment by promoting insulin signaling.

Dataset Information

Big dynorphin is a neuroprotector scaffold against amyloid β-peptide aggregation and cell toxicity.

Publications

Big dynorphin is a neuroprotector scaffold against amyloid β-peptide aggregation and cell toxicity.

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