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Mitochondrial Deficits With Neural and Social Damage in Early-Stage Alzheimer's Disease Model Mice
Afzal Misrani1,2,3, Sidra Tabassum1,2,3, Qingwei Huo4
1Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, China.
Abstract:
Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide. Mitochondrial dysfunction is thought to be an early event in the onset and progression of AD; however, the precise underlying mechanisms remain unclear. In this study, we investigated mitochondrial proteins involved in organelle dynamics, morphology and energy production in the medial prefrontal cortex (mPFC) and hippocampus (HIPP) of young (1∼2 months), adult (4∼5 months) and aged (9∼10, 12∼18 months) APP/PS1 mice. We observed increased levels of mitochondrial fission protein, Drp1, and decreased levels of ATP synthase subunit, ATP5A, leading to abnormal mitochondrial morphology, increased oxidative stress, glial activation, apoptosis, and altered neuronal morphology as early as 4∼5 months of age in APP/PS1 mice. Electrophysiological recordings revealed abnormal miniature excitatory postsynaptic current in the mPFC together with a minor connectivity change between the mPFC and HIPP, correlating with social deficits. These results suggest that abnormal mitochondrial dynamics, which worsen with disease progression, could be a biomarker of early-stage AD. Therapeutic interventions that improve mitochondrial function thus represent a promising approach for slowing the progression or delaying the onset of AD.
Insights
Mitochondrial dysfunction, characterized by abnormal dynamics and morphology, is an early biomarker in Alzheimer's disease (AD). Targeting mitochondrial health may offer therapeutic strategies for slowing AD progression.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Alzheimer's disease (AD) is a leading neurodegenerative disorder.
- Mitochondrial dysfunction is implicated in early AD pathogenesis.
- Mechanisms linking mitochondrial changes to AD remain unclear.
Purpose of the Study:
- Investigate mitochondrial proteins in organelle dynamics, morphology, and energy production.
- Examine these changes in the medial prefrontal cortex (mPFC) and hippocampus (HIPP) of APP/PS1 mice across different age groups.
- Determine the correlation between mitochondrial alterations and early AD symptoms.
Main Methods:
- Studied mitochondrial proteins (e.g., Drp1, ATP5A) in APP/PS1 mouse models.
- Analyzed mitochondrial morphology, oxidative stress, glial activation, apoptosis, and neuronal morphology.
- Performed electrophysiological recordings in the mPFC and assessed mPFC-HIPP connectivity.
- Correlated findings with observed social deficits.
Main Results:
- Increased mitochondrial fission protein (Drp1) and decreased ATP synthase subunit (ATP5A) observed in APP/PS1 mice.
- Abnormal mitochondrial morphology, oxidative stress, glial activation, apoptosis, and altered neuronal morphology detected early (4-5 months).
- Abnormal miniature excitatory postsynaptic currents in mPFC and social deficits correlated with mitochondrial changes.
Conclusions:
- Abnormal mitochondrial dynamics serve as an early biomarker for Alzheimer's disease.
- These mitochondrial alterations worsen with disease progression.
- Mitochondrial function improvement presents a promising therapeutic avenue for AD.
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