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Alterations of Transcription of Genes Coding Anti-oxidative and Mitochondria-Related Proteins in Amyloid ? Toxicity: Relevance to Alzheimer's Disease.

ABSTRACT: A growing body of evidence indicates that pathological forms of amyloid beta (A?) peptide contribute to neuronal degeneration and synaptic loss in Alzheimer's disease (AD). In this study, we investigated the impact of exogenous A?1-42 oligomers (A?O) and endogenously liberated A? peptides on transcription of genes for anti-oxidative and mitochondria-related proteins in cell lines (neuronal SH-SY5Y and microglial BV2) and in brain cortex of transgenic AD (Tg-AD) mice, respectively. Our results demonstrated significant A?O-evoked changes in transcription of genes in SH-SY5Y cells, where A?O enhanced expression of Sod1, Cat, mt-Nd1, Bcl2, and attenuated Sirt5, Sod2 and Sdha. In BV2 line, A?O increased the level of mRNA for Sod2, Dnm1l, Bcl2, and decreased for Gpx4, Sirt1, Sirt3, mt-Nd1, Sdha and Mfn2. Then, A?O enhanced free radicals level and impaired mitochondrial membrane potential only in SH-SY5Y cells, but reduced viability of both cell types. Inhibitor of poly(ADP-ribose)polymerase-1 and activator of sirtuin-1 more efficiently enhanced viability of SH-SY5Y than BV2 affected by A?O. Analysis of brain cortex of Tg-AD mice confirmed significant downregulation of Sirt1, Mfn1 and mt-Nd1 and upregulation of Dnm1l. In human AD brain, changes of microRNA pattern (miRNA-9, miRNA-34a, miRNA-146a and miRNA-155) seem to be responsible for decrease in Sirt1 expression. Overall, our results demonstrated a diverse response of neuronal and microglial cells to A?O toxicity. Alterations of genes encoding Sirt1, Mfn1 and Drp1 in an experimental model of AD suggest that modulation of mitochondria dynamics and Sirt1, including miRNA strategy, may be crucial for improvement of AD therapy.

SUBMITTER: Cieslik M

PROVIDER: S-EPMC7061023 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Alterations of Transcription of Genes Coding Anti-oxidative and Mitochondria-Related Proteins in Amyloid β Toxicity: Relevance to Alzheimer's Disease.

Cieślik Magdalena M Czapski Grzegorz A GA Wójtowicz Sylwia S Wieczorek Iga I Wencel Przemysław L PL Strosznajder Robert P RP Jaber Vivian V Lukiw Walter J WJ Strosznajder Joanna B JB

Molecular neurobiology 20191116 3

A growing body of evidence indicates that pathological forms of amyloid beta (Aβ) peptide contribute to neuronal degeneration and synaptic loss in Alzheimer's disease (AD). In this study, we investigated the impact of exogenous Aβ<sub>1-42</sub> oligomers (AβO) and endogenously liberated Aβ peptides on transcription of genes for anti-oxidative and mitochondria-related proteins in cell lines (neuronal SH-SY5Y and microglial BV2) and in brain cortex of transgenic AD (Tg-AD) mice, respectively. Our ...[more]

PMID: 31734880

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Project description:The interaction of amyloid-beta (Abeta) and redox-active metals, two important biomarkers present in the senile plaques of Alzheimer's disease (AD) brain, has been suggested to enhance the Abeta aggregation or facilitate the generation of reactive oxygen species (ROS). This study investigates the nature of the interaction between the metal-binding domain of Abeta, viz., Abeta(1-16), and the Fe(III) or Fe(II) complex with nitrilotriacetic acid (NTA). Using electrospray ionization mass spectrometry (ESI-MS), the formation of a ternary complex of Abeta(1-16), Fe(III), and NTA with a stoichiometry of 1:1:1 was identified. MS also revealed that the NTA moiety can be detached via collision-induced dissociation. The cumulative dissociation constants of both Abeta-Fe(III)-NTA and Abeta-Fe(II)-NTA complexes were deduced to be 6.3 x 10(-21) and 5.0 x 10(-12) M(2), respectively, via measurement of the fluorescence quenching of the sole tyrosine residue on Abeta upon formation of the complex. The redox properties of these two complexes were investigated by cyclic voltammetry. The redox potential of the Abeta-Fe(III)-NTA complex was found to be 0.03 V versus Ag/AgCl, which is negatively shifted by 0.54 V when compared to the redox potential of free Fe(III)/Fe(II). Despite such a large potential modulation, the redox potential of the Abeta-Fe(III)-NTA complex is still sufficiently high for a range of redox reactions with cellular species to occur. The Abeta-Fe(II)-NTA complex electrogenerated from the Abeta-Fe(III)-NTA complex was also found to catalyze the reduction of oxygen to produce H(2)O(2). These findings provide significant insight into the role of iron and Abeta in the development of AD. The binding of iron by Abeta modulates the redox potential to a level at which its redox cycling occurs. In the presence of a biological reductant (antioxidant), redox cycling of iron could disrupt the redox balance within the cellular milieu. As a consequence, not only is ROS continuously produced, but oxygen and biological reductants can also be depleted. A cascade of biological processes can therefore be affected. In addition, the strong binding affinity of Abeta toward Fe(III) and Fe(II) indicates Abeta could compete for iron against other iron-containing proteins. In particular, its strong affinity for Fe(II), which is 8 orders of magnitude stronger than that of transferrin, would greatly interfere with iron homeostasis.

Dataset Information

Alterations of Transcription of Genes Coding Anti-oxidative and Mitochondria-Related Proteins in Amyloid ? Toxicity: Relevance to Alzheimer's Disease.

Publications

Alterations of Transcription of Genes Coding Anti-oxidative and Mitochondria-Related Proteins in Amyloid β Toxicity: Relevance to Alzheimer's Disease.

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