Dataset Information

Mitochondria-specific accumulation of amyloid β induces mitochondrial dysfunction leading to apoptotic cell death.

ABSTRACT: Mitochondria are best known as the essential intracellular organelles that host the homeostasis required for cellular survival, but they also have relevance in diverse disease-related conditions, including Alzheimer's disease (AD). Amyloid β (Aβ) peptide is the key molecule in AD pathogenesis, and has been highlighted in the implication of mitochondrial abnormality during the disease progress. Neuronal exposure to Aβ impairs mitochondrial dynamics and function. Furthermore, mitochondrial Aβ accumulation has been detected in the AD brain. However, the underlying mechanism of how Aβ affects mitochondrial function remains uncertain, and it is questionable whether mitochondrial Aβ accumulation followed by mitochondrial dysfunction leads directly to neuronal toxicity. This study demonstrated that an exogenous Aβ(1-42) treatment, when applied to the hippocampal cell line of mice (specifically HT22 cells), caused a deleterious alteration in mitochondria in both morphology and function. A clathrin-mediated endocytosis blocker rescued the exogenous Aβ(1-42)-mediated mitochondrial dysfunction. Furthermore, the mitochondria-targeted accumulation of Aβ(1-42) in HT22 cells using Aβ(1-42) with a mitochondria-targeting sequence induced the identical morphological alteration of mitochondria as that observed in the APP/PS AD mouse model and exogenous Aβ(1-42)-treated HT22 cells. In addition, subsequent mitochondrial dysfunctions were demonstrated in the mitochondria-specific Aβ(1-42) accumulation model, which proved indistinguishable from the mitochondrial impairment induced by exogenous Aβ(1-42)-treated HT22 cells. Finally, cellular toxicity was directly induced by mitochondria-targeted Aβ(1-42) accumulation, which mimics the apoptosis process in exogenous Aβ(1-42)-treated HT22 cells. Taken together, these results indicate that mitochondria-targeted Aβ(1-42) accumulation is the necessary and sufficient condition for Aβ-mediated mitochondria impairments, and leads directly to cellular death rather than along with other Aβ-mediated signaling alterations.

SUBMITTER: Cha MY

PROVIDER: S-EPMC3325919 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Background & aimsIn cirrhosis, astrocytic swelling is believed to be the principal mechanism of ammonia neurotoxicity leading to hepatic encephalopathy (HE). The role of neuronal dysfunction in HE is not clear. We aimed to explore the impact of hyperammonaemia on mitochondrial function in primary co-cultures of neurons and astrocytes and in acute brain slices of cirrhotic rats using live cell imaging.MethodsTo primary cocultures of astrocytes and neurons, low concentrations (1 and 5 μM) of NH4Cl were applied. In rats with bile duct ligation (BDL)-induced cirrhosis, a model known to induce hyperammonaemia and minimal HE, acute brain slices were studied. One group of BDL rats was treated twice daily with the ammonia scavenger ornithine phenylacetate (OP; 0.3 g/kg). Fluorescence measurements of changes in mitochondrial membrane potential (Δψm), cytosolic and mitochondrial reactive oxygen species (ROS) production, lipid peroxidation (LP) rates, and cell viability were performed using confocal microscopy.ResultsNeuronal cultures treated with NH4Cl exhibited mitochondrial dysfunction, ROS overproduction, and reduced cell viability (27.8 ± 2.3% and 41.5 ± 3.7%, respectively) compared with untreated cultures (15.7 ± 1.0%, both p <0.0001). BDL led to increased cerebral LP (p = 0.0003) and cytosolic ROS generation (p <0.0001), which was restored by OP (both p <0.0001). Mitochondrial function was severely compromised in BDL, resulting in hyperpolarisation of Δψm with consequent overconsumption of adenosine triphosphate and augmentation of mitochondrial ROS production. Administration of OP restored Δψm. In BDL animals, neuronal loss was observed in hippocampal areas, which was partially prevented by OP.ConclusionsOur results elucidate that low-grade hyperammonaemia in cirrhosis can severely impact on brain mitochondrial function. Profound neuronal injury was observed in hyperammonaemic conditions, which was partially reversible by OP. This points towards a novel mechanism of HE development.Lay summaryThe impact of hyperammonaemia, a common finding in patients with liver cirrhosis, on brain mitochondrial function was investigated in this study. The results show that ammonia in concentrations commonly seen in patients induces severe mitochondrial dysfunction, overproduction of damaging oxygen molecules, and profound injury and death of neurons in rat brain cells. These findings point towards a novel mechanism of ammonia-induced brain injury in liver failure and potential novel therapeutic targets.

Project description:The prevention or delay of brain senescence would enhance the quality of life for older persons. We investigated the effects of soybean extracts in senescence-accelerated (SAMP10) mice. This mouse is a model of brain senescence with a short life span, cerebral atrophy and cognitive dysfunction. Mice were fed a diet containing soybean extracts from 1 to 12 months of age. The effects of green and yellow soybean extracts were compared with a control diet without soybean extracts. Cognitive functions were higher in aged mice fed green soybean than age-matched control mice and mice fed yellow soybean. We further investigated transcriptome of the SAMP10 hippocampus indicated that expression levels of 36 genes were significantly higher and 19 genes were lower in mice that ingested green soybean than in mice that ingested yellow soybean. Some of the evidences were reconfirmed by real time PCR analysis; the levels of Cdh1 and Ptgds mRNA were significantly higher and that the level of Aplp1 was significantly lower in aged SAMP10 mice fed green soybean than mice ingested yellow soybean and control mice. Additionally, the amount of amyloid beta 40 and 42 was lower in the insoluble fraction of aged SAMP10 mice fed green soybean than control mice and mice fed yellow soybean, although the levels of amyloid beta 40 and 42 in the soluble fraction were not different. Lipocalin-type prostaglandin D2 synthase (L-PGDS) has been proposed as the endogenous amyloid beta - chaperone, suggesting that amyloid aggregation was lower in mice fed green soybean than control mice and mice fed yellow soybean. These results indicate that the intake of green soybean improved cognitive function in aged mice, and suppressed amyloid beta accumulation. Green soybean might help healthy aging of the brain in older persons. The effect of green and yellow soybean extracts on cognitive function in aged SAMP10 mice. Mice were fed a CE-2 diet containing 3.0% soybean extracts taken from both yellow and green soybean species, from 1 to 12 months of age. Total RNA was extracted from the stored hippocampus for DNA microarray analysis.

Dataset Information

Mitochondria-specific accumulation of amyloid β induces mitochondrial dysfunction leading to apoptotic cell death.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets