Dataset Information

Aqua-soluble DDQ reduces the levels of Drp1 and A? and inhibits abnormal interactions between A? and Drp1 and protects Alzheimer's disease neurons from A?- and Drp1-induced mitochondrial and synaptic toxicities.

ABSTRACT: The purpose of our study was to develop a therapeutic target that can reduce A? and Drp1 levels, and also can inhibit abnormal interactions between A? and Drp1 in AD neurons. To achieve this objective, we designed various compounds and their 3-dimensional molecular structures were introduced into A? and Drp1 complex and identified their inhibitory properties against A?-Drp1 interaction. Among all, DDQ was selected for further investigation because of 1) its best docking score and 2) its binding capability at interacting sites of Drp1 and A? complex. We synthesized DDQ using retro-synthesis and analyzed its structure spectrally. Using biochemical, molecular biology, immunostaining and transmission electron microscopy (TEM) methods, we studied DDQ's beneficial effects in AD neurons. We measured the levels of A? and Drp1, A? and Drp1 interaction, mRNA and protein levels of mitochondrial dynamics, biogenesis and synaptic genes, mitochondrial function and cell viability and mitochondrial number in DDQ-treated and untreated AD neurons. Our qRT-PCR and immunoblotting analysis revealed that reduced levels of mitochondrial fission and increased fusion, biogenesis and synaptic genes in DDQ-treated AD neurons. Our immunoblotting and immunostaining analyses revealed that A? and Drp1 levels were reduced in DDQ-treated AD neurons. Interaction between A? and Drp1 is reduced in DDQ-treated AD neurons. A?42 levels were significantly reduced in DDQ-treated mutant APPSwe/Ind cells. Mitochondrial number is significantly reduced and mitochondrial length is significantly increased. Mitochondrial function and cell viability were maintained in AD neurons treated with DDQ. These observations indicate that DDQ reduces excessive mitochondrial fragmentation, enhances fusion, biogenesis and synaptic activity and reduces A?42 levels and protects AD neurons against A?-induced mitochondrial and synaptic toxicities.

SUBMITTER: Kuruva CS

PROVIDER: S-EPMC5886305 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Aqua-soluble DDQ reduces the levels of Drp1 and Aβ and inhibits abnormal interactions between Aβ and Drp1 and protects Alzheimer's disease neurons from Aβ- and Drp1-induced mitochondrial and synaptic toxicities.

Kuruva Chandra Sekhar CS Manczak Maria M Yin Xiangling X Ogunmokun Gilbert G Reddy Arubala P AP Reddy P Hemachandra PH

Human molecular genetics 20170901 17

The purpose of our study was to develop a therapeutic target that can reduce Aβ and Drp1 levels, and also can inhibit abnormal interactions between Aβ and Drp1 in AD neurons. To achieve this objective, we designed various compounds and their 3-dimensional molecular structures were introduced into Aβ and Drp1 complex and identified their inhibitory properties against Aβ-Drp1 interaction. Among all, DDQ was selected for further investigation because of 1) its best docking score and 2) its binding ...[more]

PMID: 28854701

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Project description:The purpose of this study is to study the neuroprotective role of selective serotonin reuptake inhibitor (SSRI), citalopram, against Alzheimer's disease (AD). Multiple SSRIs, including citalopram, are reported to treat patients with depression, anxiety and AD. However, their protective cellular mechanisms have not been studied completely. In the current study, we investigated the protective role of citalopram against impaired mitochondrial dynamics, defective mitochondrial biogenesis, defective mitophagy and synaptic dysfunction in immortalized mouse primary hippocampal cells (HT22) expressing mutant APP (SWI/IND) mutations. Using quantitative RT-PCR, immunoblotting, biochemical methods and transmission electron microscopy methods, we assessed mutant full-length APP/C-terminal fragments and Aβ levels and mRNA and protein levels of mitochondrial dynamics, biogenesis, mitophagy and synaptic genes in mAPP-HT22 cells and mAPP-HT22 cells treated with citalopram. Increased levels of mRNA levels of mitochondrial fission genes, decreased levels of fusion biogenesis, autophagy, mitophagy and synaptic genes were found in mAPP-HT22 cells relative to WT-HT22 cells. However, mAPP-HT22 cells treated with citalopram compared to mAPP-HT22 cells revealed reduced levels of the mitochondrial fission genes, increased fusion, biogenesis, autophagy, mitophagy and synaptic genes. Our protein data agree with mRNA levels. Transmission electron microscopy revealed significantly increased mitochondrial numbers and reduced mitochondrial length in mAPP-HT22 cells; these were reversed in citalopram-treated mAPP-HT22 cells. Cell survival rates were increased in citalopram-treated mAPP-HT22 relative to citalopram-untreated mAPP-HT22. Further, mAPP and C-terminal fragments werealso reduced in citalopram-treated cells. These findings suggest that citalopram reduces mutant APP and Aβ and mitochondrial toxicities and may have a protective role of mutant APP and Aβ-induced injuries in patients with depression, anxiety and AD.

Dataset Information

Aqua-soluble DDQ reduces the levels of Drp1 and A? and inhibits abnormal interactions between A? and Drp1 and protects Alzheimer's disease neurons from A?- and Drp1-induced mitochondrial and synaptic toxicities.

Publications

Aqua-soluble DDQ reduces the levels of Drp1 and Aβ and inhibits abnormal interactions between Aβ and Drp1 and protects Alzheimer's disease neurons from Aβ- and Drp1-induced mitochondrial and synaptic toxicities.

Similar Datasets

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