Extracellular PHF-tau modulates astrocyte mitochondrial dynamics and mediates neuronal connectivity

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Tau protein stabilizes microtubules but can aggregate pathologically.
• Extracellular aggregated tau (ePHF-tau) effects on neurons and astrocytes are understudied.
• Understanding ePHF-tau's impact is crucial for neurodegenerative disease research.

Purpose of the Study:

• To investigate the effects of extracellular paired helical filaments of tau (ePHF-tau) on neurons and astrocytes.
• To analyze changes in neurites, synapses, and mitochondrial proteomic profiles following ePHF-tau treatment.
• To observe mitochondrial dynamics in neurons and astrocytes over time.

Main Methods:

• Primary rat neuroglia cultures treated with human ePHF-tau (2N4R).
• Microscopy for neurite and synapse analysis.
• Proteomic profiling of synaptosomes and mitochondria.
• High-speed imaging of mitochondrial behavior in isolated neurons and astrocytes.

Main Results:

• Astrocytes cleared ePHF-tau within two days.
• ePHF-tau induced increased synaptic vesicle production, suggesting excitotoxicity.
• Astrocytes showed increased mitochondrial biogenesis and turnover; neurons had minor oxidative stress.
• Astrocyte-specific tau or PGC1alpha overexpression mimicked synaptic changes.

Conclusions:

• Astrocyte accumulation of PHF-tau alters mitochondrial biogenesis, influencing synaptic regulation.
• Astrocyte adaptation to tauopathy modulates synaptic dynamics.
• Therapeutic strategies targeting astrocytic mechanisms in tauopathies are promising.