Extracellular tau oligomers exert neurocytotoxicity by triggering mitochondrial dysfunction

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Abnormal tau aggregation is central to neurodegenerative diseases like Alzheimer's disease (AD).
• Extracellular tau and its cell-to-cell spread contribute to neurotoxicity.
• Current therapeutic strategies aim to reduce extracellular tau levels.

Purpose of the Study:

• To elucidate the molecular mechanisms behind extracellular tau oligomer cytotoxicity.
• To identify potential therapeutic targets for tau-related neurodegenerative diseases.

Main Methods:

• Transmission electron microscopy for tau oligomer morphology.
• Cell viability assays (CCK-8), microscopy for localization, and apoptosis detection (Hoechst/PI, Annexin V/PI, flow cytometry).
• Mitochondrial function assessment (JC-1, DCFH-DA, Fluo-4 AM) and Western blot for apoptosis/autophagy pathways.

Main Results:

• Extracellular tau oligomers reduced SH-SY5Y cell viability and induced apoptosis.
• Tau oligomers entered cells, decreased mitochondrial membrane potential, increased reactive oxygen species, and disrupted calcium homeostasis.
• Cytotoxicity was linked to mitochondrial apoptosis induction and mitophagy blockade.

Conclusions:

• A molecular mechanism for extracellular tau oligomer cytotoxicity involving mitochondrial dysfunction and apoptosis was identified.
• These findings highlight mitochondrial apoptosis and mitophagy blockade as key contributors to tau toxicity.
• The study provides a potential therapeutic target for tau-related diseases.