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Updated: Aug 14, 2025
Author Spotlight: Decoding Mitochondrial Aging
Published on: June 30, 2023
Early Mitochondrial Defects in the 5xFAD Mouse Model of Alzheimer's Disease
Neelam Sharma1, Rupkatha Banerjee1, Ronald L Davis1
1Department of Neuroscience, University of Florida Scripps Biomedical Research Institute, Jupiter, FL, USA.
Background:
Mitochondrial (MT) dysfunction is a hallmark of Alzheimer's disease (AD). Amyloid-β protein precursor and amyloid-β peptides localize to MT and lead to MT dysfunction in familial forms of AD. This dysfunction may trigger subsequent types of pathology.
Objective:
To identify the MT phenotypes that occur early in order to help understand the cascade of AD pathophysiology.
Methods:
The 5xFAD mouse model was used to explore the time course of MT pathologies in both sexes. Protein biomarkers for MT dynamics were measured biochemically and MT function was measured using oxygen consumption and ATP assays.
Results:
We discovered progressive alterations in mitochondrial dynamics (biogenesis, fission, fusion, and mitophagy) and function (O2 consumption, ATP generation, and Ca2+ import) in the hippocampus of 5xFAD mice in both sexes as early as 2 months of age. Thus, mitochondrial dynamics and function become altered at young ages, consistent with an early role for mitochondria in the AD pathological cascade.
Conclusion:
Our study offers the baseline information required to understand the hierarchical relationship between the multiple pathologies that develop in this mouse model and provides early biomarkers for MT dysfunction. This will aid in dissecting the temporal cascade of pathologies, understanding sex-specific differences, and in testing the efficacy of putative mitochondrial therapeutics.
Insights
Mitochondrial dysfunction occurs early in Alzheimer's disease (AD) pathology. This study in 5xFAD mice reveals early alterations in mitochondrial dynamics and function, offering insights into AD progression and potential therapeutics.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Alzheimer's Disease Research
Background:
- Mitochondrial (MT) dysfunction is a key feature of Alzheimer's disease (AD).
- Amyloid precursor protein and peptides in AD localize to mitochondria, causing dysfunction that may initiate further pathology.
- Understanding early MT changes is crucial for unraveling AD's complex pathophysiology.
Purpose of the Study:
- To identify early mitochondrial phenotypes in Alzheimer's disease (AD) pathogenesis.
- To investigate the temporal cascade of mitochondrial alterations in a mouse model of AD.
- To establish early biomarkers for mitochondrial dysfunction in AD.
Main Methods:
- Utilized the 5xFAD mouse model to study mitochondrial pathologies over time in both sexes.
- Assessed mitochondrial dynamics using protein biomarkers.
- Measured mitochondrial function via oxygen consumption and ATP assays.
Main Results:
- Progressive alterations in mitochondrial dynamics (biogenesis, fission, fusion, mitophagy) were observed in 5xFAD mice as early as 2 months of age.
- Mitochondrial function, including O2 consumption, ATP generation, and Ca2+ import, was altered early in both sexes.
- These findings indicate that mitochondrial dynamics and function are affected at a young age, supporting an early role in the AD pathological cascade.
Conclusions:
- The study provides essential baseline data for understanding the interplay of pathologies in the 5xFAD model.
- Identified early biomarkers for mitochondrial dysfunction, aiding in dissecting the temporal sequence of AD pathologies.
- Findings will facilitate research into sex-specific differences and the evaluation of mitochondrial therapeutics for AD.
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