Related Experiment Video
Updated: Feb 23, 2026
Author Spotlight: Decoding Mitochondrial Aging
Published on: June 30, 2023
Mitochondrial dysfunction in the APP/PSEN1 mouse model of Alzheimer's disease and a novel protective role for
Shilpy Dixit1, Joshua P Fessel2, Fiona E Harrison3
1Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA; Graduate Program in Neuroscience, Vanderbilt University, Nashville, Tennessee 37232, USA.
Abstract:
Mitochondrial dysfunction is elevated in very early stages of Alzheimer's disease and exacerbates oxidative stress, which contributes to disease pathology. Mitochondria were isolated from 4-month-old wild-type mice, transgenic mice carrying the APPSWE and PSEN1dE9 mutations, mice with decreased brain and mitochondrial ascorbate (vitamin C) via heterozygous knockout of the sodium dependent vitamin C transporter (SVCT2+/-) and transgenic APP/PSEN1 mice with heterozygous SVCT2 expression. Mitochondrial isolates from SVCT2+/- mice were observed to consume less oxygen using high-resolution respirometry, and also exhibited decreased mitochondrial membrane potential compared to wild type isolates. Conversely, isolates from young (4 months) APP/PSEN1 mice consumed more oxygen, and exhibited an increase in mitochondrial membrane potential, but had a significantly lower ATP/ADP ratio compared to wild type isolates. Greater levels of reactive oxygen species were also produced in mitochondria isolated from both APP/PSEN1 and SVCT2+/- mice compared to wild type isolates. Acute administration of ascorbate to mitochondria isolated from wild-type mice increased oxygen consumption compared with untreated mitochondria suggesting ascorbate may support energy production. This study suggests that both presence of amyloid and ascorbate deficiency can contribute to mitochondrial dysfunction, even at an early, prodromal stage of Alzheimer's disease, although occurring via different pathways. Ascorbate may, therefore, provide a useful preventative strategy against neurodegenerative disease, particularly in populations most at risk for Alzheimer's disease in which stores are often depleted through mitochondrial dysfunction and elevated oxidative stress.
Insights
Early Alzheimer's disease involves mitochondrial dysfunction and oxidative stress. Both amyloid presence and vitamin C deficiency impair mitochondria, suggesting vitamin C as a potential preventative strategy against neurodegeneration.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Mitochondrial dysfunction and oxidative stress are early indicators in Alzheimer's disease (AD).
- These factors contribute significantly to AD pathology.
- Understanding early molecular changes is crucial for developing preventative strategies.
Purpose of the Study:
- To investigate the roles of amyloid-beta and ascorbate (vitamin C) deficiency in early-stage mitochondrial dysfunction in Alzheimer's disease.
- To explore the impact of these factors on mitochondrial respiration, membrane potential, ATP production, and reactive oxygen species generation.
- To assess the potential of ascorbate as a preventative measure against AD-related neurodegeneration.
Main Methods:
- Mitochondria were isolated from young (4-month-old) wild-type mice, APP/PSEN1 transgenic mice, SVCT2+/- mice (impaired vitamin C transport), and combined APP/PSEN1/SVCT2+/- mice.
- High-resolution respirometry was used to measure oxygen consumption.
- Mitochondrial membrane potential, ATP/ADP ratio, and reactive oxygen species (ROS) levels were assessed.
- Acute ascorbate administration was tested on wild-type mitochondria.
Main Results:
- Mitochondria from SVCT2+/- mice showed reduced oxygen consumption and lower membrane potential.
- Mitochondria from APP/PSEN1 mice exhibited increased oxygen consumption, elevated membrane potential, but decreased ATP/ADP ratio.
- Both APP/PSEN1 and SVCT2+/- mitochondria produced higher levels of reactive oxygen species compared to wild-type.
- Ascorbate administration enhanced oxygen consumption in wild-type mitochondria.
Conclusions:
- Both amyloid presence and ascorbate deficiency contribute to mitochondrial dysfunction in early Alzheimer's disease, albeit through distinct mechanisms.
- These dysfunctions manifest as altered energy metabolism and increased oxidative stress.
- Ascorbate shows potential as a preventative strategy for neurodegenerative diseases, especially in at-risk populations with depleted vitamin C levels.
More Related Videos
11:47Treating SCA1 Mice with Water-Soluble Compounds to Non-Specifically Boost Mitochondrial Function
Published on: January 22, 2017
06:07Author Spotlight: Establishing a New Fluorescence-Based Protocol for In Vivo Mitochondrial Morphology Analysis in Parkinson's Disease
Published on: June 23, 2023
Related Concept Videos
01:46Electron Transport Chain: Complex I and II
ROS generation is regulated and maintained at moderate levels necessary...
01:37Mitochondria