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ScFv T1 Protects Against Mitochondrial Damage of SH-SY5Y Cells Caused by Extracellular Tau Aggregates
Zongbao Wang1, Xinyi Jiang1, Jingye Lin1
1Gene Engineering and Biotechnology Beijing Key Laboratory, The Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
Abstract:
Mitochondria are essential organelles that perform irreplaceable functions in neurons. The degeneration of neurons in Alzheimer's disease (AD) is associated with mitochondrial damage, and Tau pathology represents a significant pathogenic factor in AD. However, the relationship between Tau and mitochondrial dysfunction during neuronal degeneration remains unclear. In this study, we investigated the effects and mechanisms by which extracellular Tau aggregates induce neuronal mitochondrial damage and dysfunction. The results showed that extracellular Tau aggregates lead to structural damage of mitochondria in SH-SY5Y cells and disrupt mitochondrial homeostasis. Extracellular Tau aggregates can also cause mitochondrial oxidative stress and inhibit oxidative phosphorylation in SH-SY5Y cells. Concurrently, extracellular Tau aggregates promote neuronal death through an increase in cytochrome C, mtDNA leakage and activation of the cGAS/STING pathway. We also explored the effects of a single-chain variable fragment antibody (scFv T1) and found that scFv T1 alleviated mitochondrial damage and dysfunction by inhibiting the formation of Tau aggregates. These findings suggest that targeting Tau pathology may be crucial to address neuronal mitochondrial impairment and that reduction of the toxicity associated with extracellular Tau aggregates could help slow Tau pathology progression.
Insights
Extracellular Tau aggregates damage mitochondria and disrupt neuronal homeostasis, leading to cell death in Alzheimer's disease (AD). Targeting Tau pathology with therapies like scFv T1 may protect neurons from mitochondrial dysfunction.
Area of Science:
- Neuroscience
- Cell Biology
- Mitochondrial Biology
Background:
- Mitochondrial dysfunction is linked to neuronal degeneration in Alzheimer's disease (AD).
- Tau pathology is a key factor in AD pathogenesis.
- The precise role of Tau in mitochondrial damage during neurodegeneration is not fully understood.
Purpose of the Study:
- To investigate how extracellular Tau aggregates cause mitochondrial damage and dysfunction in neurons.
- To elucidate the mechanisms underlying Tau-induced mitochondrial impairment.
- To evaluate the therapeutic potential of targeting Tau aggregates.
Main Methods:
- Utilized SH-SY5Y cell models to study the effects of extracellular Tau aggregates.
- Assessed mitochondrial structure, homeostasis, oxidative stress, and oxidative phosphorylation.
- Investigated markers of neuronal death, including cytochrome C release, mtDNA leakage, and cGAS/STING pathway activation.
- Examined the efficacy of a single-chain variable fragment antibody (scFv T1) in mitigating Tau-induced damage.
Main Results:
- Extracellular Tau aggregates induced structural damage and disrupted mitochondrial homeostasis in SH-SY5Y cells.
- Tau aggregates caused mitochondrial oxidative stress and inhibited oxidative phosphorylation.
- Neuronal death was promoted by increased cytochrome C, mtDNA leakage, and cGAS/STING pathway activation.
- scFv T1 treatment alleviated mitochondrial damage by inhibiting Tau aggregate formation.
Conclusions:
- Extracellular Tau aggregates are a direct cause of mitochondrial damage and dysfunction in neurons.
- Tau pathology contributes to neuronal death through mechanisms involving oxidative stress and inflammatory pathways.
- Targeting extracellular Tau aggregates with agents like scFv T1 shows promise for treating Alzheimer's disease by preserving mitochondrial function.
