Abstract
Mitochondrial dysfunction with oxidative damage plays the fundamental roles in the pathogenesis of Alzheimer’s disease. In traditional Chinese medicine (TCM) practice, animal tissue-derived gelatins are often used as nootropic agents to treat cognitive deterioration and senile dementia. Tortoise plastron gelatin (TPG) and deer antler gelatin (DAG) are the two most commonly used gelatins for this purpose. This study sought to examine the effects of the two gelatins in preventing neuronal mitochondria from oxidative damage. PC12 cells, a cell line derived from rat pheochromocytoma, exposed to the neurotoxin Aβ25–35 served as an in vitro model of Alzheimer’s disease. The cells were separately pre-treated with TPG and DAG at various concentrations ranging from 6.26 µg/ml–200 µg/ml, followed by co-incubation with 20 μM Aβ25–35 for different duration. Cell viability, mitochondrial membrane potential (MMP) and ultrastructure, intracellular ATP, reactive oxygen species (ROS) and calcium (Ca2+) level, the expression of mitochondrial dynamic proteins and biomarkers of apoptosis were measured. Pretreatment with TPG and DAG reversed the Aβ-induced reduction of cell viability in a dose-dependent manner. Both TPG and DAG significantly increased MMP and ATP, alleviated the accumulation of damaged mitochondrial fragments, and normalized the aberrant expression of multiple mitochondrial dynamic proteins of the Aβ-exposed cells. Both gelatins also suppressed intracellular ROS overproduction and Ca2+ overload, overexpression of cytochrome c and pro-apoptosis biomarkers induced by the Aβ exposure. These results suggest that TPG and DAG may have the anti-dementia potential by preventing neuronal mitochondria from oxidative damage.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegeneration disorder that affects millions of people worldwide
Neuronal calcium influx further disturbs the maintenance of mitochondrial dynamics with an imbalance in mitochondrial fission and fusion, leading to aberrant expression of fissionmediated proteins, such as fission1 and dynamin-related protein 1 (Drp1), and fusion-associated proteins, such as Mitofusin 1 (Mfn1), Mitofusin 2 (Mfn2), and Optic atrophy 1 (Opa1) (Ishihara et al, 2004; Losón et al, 2013)
This study revealed that the Aβ25–35 exposure resulted in a dramatic increase of intracellular Ca2+ level, rapid overproduction of reactive oxygen species (ROS) and cellular and mitochondrial damage, manifesting as reduced cell viability, mitochondrial fragmentation, increased cytochrome c level, and decreased membrane potential (MMP)
Summary
Alzheimer’s disease (AD) is a progressive neurodegeneration disorder that affects millions of people worldwide. During the evolution of AD, mitochondria suffer profound alterations, manifesting as morphological damage, decreased ATP generation, and increased production of reactive oxygen species (ROS) (Lin and Beal, 2006). An excessive ROS production, in turn, exacerbates mitochondrial dysfunction with decreased mitochondrial membrane potential (MMP) and intracellular calcium (Ca2+) overflow (Manczak et al, 2010; Tönnies and Trushina, 2017), resulting in the release of apoptotic factors, such as cytochrome c, an apoptotic mediator in the organelles and procaspase-9 and caspase-3, the two pro-apoptotic factors in response to apoptotic signals (Hengartner, 2000; Giorgi et al, 2012). Neuronal calcium influx further disturbs the maintenance of mitochondrial dynamics with an imbalance in mitochondrial fission and fusion, leading to aberrant expression of fissionmediated proteins, such as fission (fis1) and dynamin-related protein 1 (Drp1), and fusion-associated proteins, such as Mitofusin 1 (Mfn1), Mitofusin 2 (Mfn2), and Optic atrophy 1 (Opa1) (Ishihara et al, 2004; Losón et al, 2013)
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